[Poisoning by irreversible cholinesterase inhibitors; cholinesterase reactivators as antidotes].
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Antidotes↗
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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↗
Drug interactions with cholinesterase inhibitors.
Cholinesterase inhibitors are used for the symptomatic treatment of patients with Alzheimer's disease. This population often has numerous comorbidities and receives treatment with multiple medications. The astute clinician should remain mindful of possible drug interactions, both pharmacokinetic and pharmacodynamic, that may occur with concomitant treatment. Although pharmacokinetic interactions have been reported, pharmacodynamic interactions play a far greater role in the significance of drug interactions, with anticholinergic medications being most concerning. Commonly prescribed medications, such as antihistamines and tricyclic antidepressants, often have anticholinergic properties that alone or in combination with one another can antagonise the effects of cholinesterase inhibitors. Other medication classes such as antipsychotics and cholinergic agents may also result in pharmacodynamic interactions. However, for the most part, cholinesterase inhibitors can be used safely in combination with other medications.
Aged↗
Activation and blockade of cardiac muscarinic receptors by endogenous acetylcholine and cholinesterase inhibitors.
Cholinesterase inhibitors are known to potentiate the effects of acetylcholine (ACh) and vagal stimulation on the myocardium. The studies presented here demonstrate that cholinesterase inhibitors (ChEI) also have activity in isolated atria in the absence of extrinsic cholinergic stimulation and that, depending on the ChEI, either indirect stimulation or direct blockade of cardiac muscarinic receptors can occur. Muscarinic agonists inhibit cyclic AMP formation in atria and the ChEIs physostigmine, neostigmine and echothiophate likewise produce a marked attenuation of isoproterenol-stimulated cyclic AMP accumulation The effect of physostigmine appears to result from muscarinic receptor activation by endogenous ACh as it is blocked by atropine. In contrast, the ChEI ambenonium does not stimulate but instead blocks muscarinic receptors coupled to cyclic AMP accumulation. Radioligand binding studies provide direct evidence that both ambenonium and demecarium are relatively potent muscarinic receptor antagonists, whereas physostigmine and other ChEI have little direct receptor activity. Physostigmine and ambenonium also have different effects on heart rate in vivo, the former potentiating and the latter apparently blocking vagal tone. The inhibition of cyclic AMP formation produced by physostigmine can be used as a measure of the concentration of endogenous ACh available at muscarinic receptor sites. Physostigmine blocks cyclic AMP formation in atria incubated in the absence of calcium or in the presence of tetrodotoxin, suggesting that endogenous ACh is spontaneously released in the absence of neuronal activity or depolarization-secretion coupling.
Acetylcholine↗
[Cholinergic deficiency syndrome as an indicator for the cholinesterase inhibitors].
Cholinesterase inhibitors are licensed for the treatment of dementia in Alzheimer's disease. In clinical practice, these drugs have little effect on the cognitive symptoms of dementia. Several studies report a beneficial effect of cholinesterase inhibitors on neuropsychiatric symptoms. We hypothesise that symptoms such as the impairment of attention and concentration, anxiety, restlessness and hallucinations, delineate a specific central cholinergic deficiency syndrome. It is postulated that this syndrome crosses boundaries of nosological entities and occurs in various neurodegenerative diseases. Symptoms resulting from cholinergic deficiency might be a much better target for treatment than cognitive deficits.
Acetylcholinesterase↗
Relationship between the temperature and endocrine changes induced by cholinesterase inhibitors.
Cholinesterase inhibitors induce changes in plasma hormones in the rat. Since these compounds induce hypothermia the question has been raised as to whether the endocrine responses are secondary to the fall in core temperature. The time course of the changes in temperature and plasma levels of corticosterone, growth hormone and prolactin have been examined following injection of diisopropylphosphofluoridate (DFP), soman or physostigmine. All three cholinesterase inhibitors caused an initial rise in corticosterone; DFP decreased growth hormone; physostigmine reduced prolactin. The time course of the hypothermia after DFP and soman did not correlate with that of the rise in corticosterone. The data do not suggest that the hormone changes are secondary to the temperature change.
Animals↗
Strategies for continued successful treatment of Alzheimer's disease: switching cholinesterase inhibitors.
Cholinesterase (ChE) inhibitors represent the standard therapeutic approach to the treatment of Alzheimer's disease (AD). However, a proportion of patients experience lack or loss of therapeutic benefit with an initial agent, or discontinue due to safety/tolerability issues. In many instances, no alternative treatment is offered once the initial agent has been stopped. Thus, for many patients, the total duration of treatment is relatively short in comparison with the chronic nature of AD. Switching medications is a common therapeutic strategy within many drug classes across many clinical areas following a lack/loss of efficacy or safety/tolerability problems, and is also an increasingly important concept in the management of AD with ChE inhibitors. A number of open-label studies, where patients were switched from donepezil to rivastigmine, have indicated that approximately 50% of patients experiencing a lack/loss of efficacy with donepezil (a selective acetylcholinesterase [AChE] inhibitor) respond to subsequent treatment with rivastigmine (a dual AChE and butyrylcholinesterase inhibitor). In these studies, rivastigmine was well tolerated, and the occurrence of safety/tolerability problems with donepezil was not predictive of similar problems with rivastigmine. In the summer of 2002, leading neurologists and psychiatrists attended a medical experts meeting to discuss the clinical importance of switching ChE inhibitors in AD. The expert panel examined available clinical data, shared clinical experiences, and discussed current clinical guidelines for switching. The panel also aimed to reach consensus on 'whom to switch', 'when to switch' and 'how to switch'. The key findings from that meeting are reported in this review.
Alzheimer Disease↗
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↗
Role of cholinesterase inhibitors in dementia care: memory clinics and cholinesterase inhibitors have their place.
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Ambulatory Care↗
The effects of a cholinesterase inhibitor are prominent in patients with fluctuating cognition: a part 3 study of the main mechanism of cholinesterase inhibitors in dementia.
Fluctuating cognition is evidenced in different forms of dementia and is accompanied by electroencephalographic (EEG) abnormalities. The authors hypothesize that cholinesterase inhibitors are effective mostly in patients with fluctuating cognition. Twenty-three patients affected by mild dementia with similar scores on Mini-Mental State Examination (MMSE), Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog), and Unified Parkinson's Disease Rating Scale evaluation were classified in a group with fluctuating cognition (n = 11) and a group of nonfluctuators (n = 12). All patients were assigned randomly to the branches of a double-blind crossover study of donepezil (DPZ), a 5 to 10-mg dose, versus vitamin E, a 2000 IU dose, for 30 days. MMSE, ADAS-cog, University of California at Los Angeles Neuropsychiatric Inventory (NPI), quantitative EEG, P3 event-related potentials, choice reaction time variability (CRTV) were assessed at baseline and at the end of treatments. At the end of the crossover study all patients received DPZ for 6 months. The dominant EEG frequency variability, low EEG frequencies amplitude, the P3 latency and jitter, CRTV, and NPI was significantly different in the fluctuating cognition group than the nonfluctuating group at baseline (P < 0.001). Short-term DPZ administration induced a significant increase in MMSE scores, reduction of ADAS-cog and of NPI scores (P < 0.003-0.001), increase of EEG alpha activity and reductions of P3 latency and jitter, dominant frequency variability and CRTV (P < 0.009-0.001) in the fluctuating cognition group, and significant increases of MMSE scores (P = 0.03) and a decrease of P3 jitter and dominant frequency variability (P < 0.034-0.041) in the nonfluctuating group. Short-term DPZ effects differed significantly between fluctuating cognition and nonfluctuating patients (0.001). Significant effects of the 6-month observation were observed only in fluctuating cognition patients. Logistic analysis showed that P3 latency predicts the effect of DPZ (P = 0.04, P < 0.01) in the crossover study, and CRTV predicts the effect at the 6-month follow-up.
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Clinically significant drug interactions with cholinesterase inhibitors: a guide for neurologists.
Cholinesterase inhibitors are the only pharmacological class indicated for the treatment of mild to moderate Alzheimer's disease. These drugs are also being used off label to treat severe cases of Alzheimer's disease or vascular dementia and other disorders. The widespread use of cholinesterase inhibitors raises the possibility of their use in combination regimens, with the subsequent risk of deleterious drug-drug interactions in high-risk populations. The purpose of this review is to present the possible sources of pharmacokinetic or pharmacodynamic drug-drug interactions involving cholinesterase inhibitors. The four cholinesterase inhibitors (tacrine, donepezil, rivastigmine and galantamine) that are currently available have different pharmacological properties that expose patients to the risk of several types of drug interactions of nonequivalent clinical relevance. The principal proven clinically relevant drug interactions involve tacrine and drugs metabolised by the cytochrome P450 (CYP) 1A2 enzyme, as well as tacrine or donepezil and antipsychotics (which results in the appearance of parkinsonian symptoms). The bioavailability of galantamine is increased by coadministration with paroxetine, ketoconazole and erythromycin. It is of interest to note that because rivastigmine is metabolised by esterases rather than CYP enzymes, unlike the other cholinesterase inhibitors, it is unlikely to be involved in pharmacokinetic drug-drug interactions. Care must be taken to reduce the risk of inducing central (excitation, agitation) or peripheral (e.g. bradycardia, loss of consciousness, digestive disorders) hypercholinergic effects via drug interactions with cholinesterase inhibitors. A review of the literature does not reveal any alarming data but does highlight the need for prudent prescription, particularly when cholinesterase inhibitors are given in combination with psychotropics or antiarrhythmics. Possible interactions involving other often coprescribed antidementia agents (e.g. memantine, antioxidants, cognitive enhancers) remain an open area requiring particularly prudent use.
Cholinesterase Inhibitors↗
Cholinesterase inhibitors and vestibular function; a study of a vestibular syndrome in guinea-pigs caused by intracarotid centripetal injection of cholinesterase inhibitors and cholinesters.
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Choline↗
[Ability of reversible cholinesterase inhibitors to support dissociative learning].
In the experiments on rats performed to study dissociated learning it was found that reversible inhibitors of cholinesterase are interchangeable. It was shown that neutralization of the behavioral effect of cholinesterase inhibitors may be induced most successfully by combined administration of M- and N-cholinergic blocking agents.
Animals↗
[Therapy of myasthenia gravis with cholinesterase inhibitors--principles and pharmacologic monitoring].
Cholinesterase inhibitors are still important in the treatment of myasthenic patients. Therapeutic principles, indications and adverse effects are discussed in detail. Methods of pharmacological monitoring had been searched over many years. Besides determination of pyridostigmine plasma concentration, erythrocyte-bound acetylcholinesterase (AChE) activity could provide a possibility to monitor therapy with cholinesterase inhibitors. 88 patients with myasthenia gravis were investigated. The results demonstrated that after pyridostigmine erythrocyte-bound as well as synaptic AChE is inhibited. Moreover, erythrocyte-bound AChE has proven to be a parameter of cholinesterase inhibitor effect. After injection of edrophonium-chloride (Tensilon) inhibition of AChE activity can be demonstrated as well. During steady pyridostigmine doses stable plasma concentrations and AChE inhibition depend on the respective dosage. Higher daily doses result in greater stability of pharmacologic parameters, whereas low daily doses lead to great interindividual differences of AChE inhibition even after equal pyridostigmine doses. Intraindividually there is no strong correlation, too. Therefore estimation of erythrocyte-bound AChE activity is not useful for routine pharmacological monitoring of cholinesterase inhibitor therapy, but may be helpful in some clinical conditions. The method provides some advantages over pyridostigmine plasma concentration, since it is applicable for other cholinesterase inhibitors, too, and since it requires less technical equipment and time.
Acetylcholinesterase↗
Increased levels of tau protein in SH-SY5Y cells after treatment with cholinesterase inhibitors and nicotinic agonists.
Several cholinesterase inhibitors used in the treatment of Alzheimer's disease (AD) have been shown to interact with an allosteric site on the nicotinic acetylcholine receptor (nAChR). A possible linkage between the phosphorylation state of tau, the major component of paired helical filaments found in AD brain, and stimulation of nAChRs by cholinesterase inhibitors and nicotinic agonists was investigated. Western blot analysis showed that treatment of SH-SY5Y cells for 72 h with the cholinesterase inhibitors tacrine (10(-5) M), donepezil (10(-5) M), and galanthamine (10(-5) M), nicotine (10(-5) M), and epibatidine (10(-7) M) increased tau levels as detected with Tau-1, AT 8, and AT 270 monoclonal antibodies and binding of [3H]epibatidine. The increase in tau immunoreactivity induced by nicotine, epibatidine, and tacrine, but not the up-regulation of nAChRs, was prevented by the antagonists d-tubocurarine and mecamylamine. Both antagonists were synergistic with the nicotinic agonists in causing up-regulation, but only d-tubocurarine showed a synergistic effect with tacrine. The increased tau immunoreactivity induced by tacrine was not prevented by atropine, indicating that in terms of cholinergic receptors, tacrine modulates tau levels mainly through interactions with nAChRs and not with muscarinic receptors. Additional work is needed to determine the exact mechanism by which cholinesterase inhibitors and nicotinic agonists modulate phosphorylation and levels of tau protein.
Alkaline Phosphatase↗
Mechanism of action of cholinesterase inhibitors in Alzheimer's disease.
Cholinesterase inhibitors, such as physostigmine and tacrine, have lately gained interest as potential drugs in the treatment of Alzheimer's disease. Already in the 1950s, it was discovered that physostigmine and tacrine were potent inhibitors of acetylcholinesterase and butyrylcholinesterase. However, later studies have shown that cholinesterase inhibitors also interact with cholinergic receptors, with sodium and potassium ion channels and effect the uptake, synthesis and release of neurotransmitters. In summary, cholinesterase inhibitors are drugs with many modes of action, which may be of advantage in the treatment of a complex disorder such as Alzheimer's disease.
Acetylcholine↗
Hypertension, white matter change and response to cholinesterase inhibitors in Alzheimer's disease.
BACKGROUND: Cholinesterase inhibitors are used to treat mild to moderate Alzheimer's disease. Their role in patients with concurrent cerebrovascular disease has been less well studied, and the influence of vascular risk factors on response to treatment is uncertain. We investigated the effect of hypertension and white matter lesions (WML) on response. METHODS: A retrospective sample of 160 consecutive out-patients who had blood pressure measured and the presence or absence of WML recorded at baseline and who completed six months treatment with a cholinesterase inhibitor was studied. Subjects scored either zero or one on the Modified Hachinski Ischaemic Scale. Subjects were assessed using the Mini-Mental State Examination (MMSE), the Digit Symbol Substitution test (DSST) and both the Instrumental Activities of Daily Living (IADL) and Social Behaviour (SB) sub-scales of the Nurses Observation Scale for Geriatric Patients (NOSGER). RESULTS: 43.9% of the total study population were classified as good responders using our criteria. Neither the presence of hypertension nor the presence of WML alone influenced outcome. However, there was a statistically significant interaction between blood pressure and WML on outcome variables on multiple analysis of variance (MANOVA) (F(4, 139) = 5.60, p < 0.0005). Subjects with both hypertension and WML deteriorate to a significantly greater extent in IADL and SB scores than any other group (p < 0.05 in each case). This effect could not be explained by age or by smoking status. CONCLUSION: Our results support the hypothesis that there is an interaction between hypertension and WML that adversely influences functional change during cholinesterase inhibitor treatment. Our results are a contrast to suggestions that subjects with vascular disease show a better response to cholinesterase inhibitors. We recommend careful exploration of factors that may influence outcome.
Activities of Daily Living↗
Age-determined changes in the effects of a newly synthetized cholinesterase inhibitor on exploratory behavior, memory and striatal cholinesterase activity in rats.
The newly synthetized cholinesterase inhibitor C-8 (a structural analogue of physostigmine) at a dose of 4 mg.kg-1 exerted no inhibitory effect on the spontaneous locomotor activity in 2-, 10- and 22-month old male Wistar rats. Upon open field test, C-8 facilitated the process of habituation in the rats of all three groups. In a passive avoidance situation (step-down and step-through) C-8 had a favorable effect on the memory of 22-month old rats mainly. C-8 inhibited the cholinesterase activity in the striatum of 2-month old rats by 29%, in 10-month old rats by 73%, and in 22-month old rats by 30%.
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