Review
Safety considerations for patients with epilepsy taking antiepileptic drugs alongside caffeine or other methylxanthine derivatives
1.
Introduction
2.
Caffeine and AEDs
3.
Is blockade of A1 adenosine receptor-mediated events
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involved in the interaction
Magdalena Chros´cin´ska-Krawczyk, Iwona Radzik, Barbara Miziak & Stanisław J Czuczwar† †
Medical University, Department of Pathophysiology, Lublin, Poland
between AEDs and caffeine? 4.
Why some AEDs are resistant to the negative impact of caffeine?
5.
Theophylline (aminophylline) and AEDs
6.
May caffeine be anticonvulsant?
7.
Does selective antagonism at A1 adenosine receptors produce comparable to methylxanthines effects upon the anticonvulsant effects of AEDs?
8.
Conclusion
9.
Expert opinion
Introduction: Antiepileptic drugs (AEDs) are widely used for the treatment of epilepsy. However, ~ 30% of patients do not remain seizure free. It is possible that methylxanthine derivatives (e.g., caffeine and theophylline) may partially account for this outcome. Areas covered: Data on the convulsive activity of methylxanthines are reviewed. The negative impact of caffeine and theophylline (or aminophylline) on the protective activity of classic and newer AEDs is also considered. Case report studies indicate that ingestion of caffeine may increase seizure frequency, which returns to baseline when the consumption of coffee or caffeine-rich drinks is terminated. However, the existing data also provide clinical evidence that caffeine may not be a trigger for precipitation of seizure activity and this discrepancy is evaluated. Expert opinion: Experimental data indicate that caffeine and aminophylline both significantly reduce the anticonvulsant activity of a number of AEDs. Clinical data are controversial. Patients with epilepsy should be advised not to take methylxanthine-containing medications. Caffeine consumption, especially accidental and in huge quantities, should be avoided in patients with epilepsy. Keywords: caffeine, drug interactions, epilepsy, methylxanthine Expert Opin. Drug Metab. Toxicol. (2014) 10(7):981-989
1.
Introduction
Caffeine (1,3,7-trimethylxanthine) is the most commonly and widely ingested stimulant. It belongs to the group of purine alkaloids and is found in beverages such as coffee, tea and many soft drinks as well as in chocolate products and desiccated coconut. Caffeine is present in appetite stimulants, analgesics and some antiviral drugs. This methylxanthine is probably the most consumed psychoactive substance in the world. It is estimated that in developed countries 90% of people ingest caffeine on a daily basis [1-4]. History of caffeine is associated with the history of coffee. The name of coffee was derived from the Arabian word ‘gahwa’, which means ‘excising tiredness’. The most dangerous complication of caffeine overdose is seizure activity which is induced in rodents in doses over 400 mg/kg [5-8]. Caffeine is a nonselective antagonist of adenosine receptors [9]. The inhibitory role of adenosine in the control of seizure activity has been well characterized [10,11]. There are four main subtypes of adenosine receptors: A1, A2A, A2B and A3. All these subtypes are coupled to G proteins, and adenosine is their endogenous ligand [12]. The greatest concentrations of A1 receptors are found in the CNS, especially in the hippocampus, human cortex, cerebellum, brain stem and spinal cord [12]. They are also found in many organs and tissues, for example, immune system [13]. The 10.1517/17425255.2014.920822 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
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2.
Article highlights. .
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. . .
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Caffeine is the most ingested stimulant, and aminophylline (and other methylxanthines) may be prescribed to epileptic patients for reasons unrelated to epilepsy. Caffeine and aminophylline reduced the anticonvulsant potential of many antiepileptic drugs in rodents. The most pronounced negative impact of methylxanthines was observed after chronic administration or after a challenging dose of caffeine, following caffeine discontinuation. Case report studies seem to support the experimental results. Other reports, however, do not confirm that caffeine may be a trigger for seizure activity. Probably, accidental ingestion of methylxanthines in high amounts may be more hazardous than habitual ingestion. Considering the results of experimental studies and some clinical data, ingestion of caffeine and curative use of methylxanthines should be limited in epileptic patients.
This box summarizes key points contained in the article.
A1 receptor activation results in sedation, anticonvulsant activity, anxiolytic effects and depression of motor activity. Further, its activation results in an inhibition of adenylyl cyclase causing a decrease in cAMP [14]. The stimulation of A2 receptor activates adenylyl cyclase and results in the release of a number of neurotransmitters: dopamine, norepinephrine, acetylcholine and glutamate [15,16]. The A2A receptors have a high affinity for adenosine and are restricted to the dopaminerich areas of the brain, for example, as the striatum [17]. Generally, A1 adenosine receptor agonists exert anticonvulsant effects in many rodent models of epilepsy [18] and are able to potentiate the anticonvulsant effects of antiepileptic drugs (AEDs) [19]. The existing data reveal that A2a adenosine receptor antagonists or agonists did not significantly modulate amygdala-kindled seizures in rats [20]. In audiogenic seizures in DBA/2 mice, the A2 receptor agonist CGS 21680 suppressed seizure activity [21]. Results reported by Zeraati et al. [22] provide evidence that A2a receptor agonist produced proconvulsive effect, prolonging after discharges in piriform cortex-kindled rats, when administered into the CA1 hippocampal field. Interestingly, A3 adenosine receptors possess much lower affinity towards adenosine when compared with the former receptor subtypes [23]. The A3 adenosine receptor agonist N6-(3-Iodobenzyl)adenosine-5¢-N-methyluronamide (IB-MECA) was anticonvulsant against pentylenetetrazol in mice but no anticonvulsant effect was noted against electroconvulsions in mice [24]. However, stimulation of A3 adenosine receptors was most likely associated with an enhancement of the protective activity of carbamazepine (CBZ) against maximal electroshock (MES)-induced convulsions in mice [25]. 982
Caffeine and AEDs
Caffeine, which is a nonselective antagonist of adenosine receptors, preferably of A1 and A2 [9], has been documented to produce seizures per se [5-7] and exerts proconvulsive effects in vitro [26]. When caffeine was given at 10 -- 20 mg/kg for postnatal days 7 -- 11, it shortened the latency to pentylenetetrazol (40 mg/kg)-induced rhythmic EEG activation. However, some anticonvulsant effects of the methylxanthine were noted when the convulsant was given at 20 mg/kg [27]. The specific epileptogenic effect of caffeine and other methylxanthines is correlated with their affinities to A1 adenosine receptors [28]. Apart from reports indicating the clear-cut convulsive potential of caffeine and other methylxanthines, there are also data available on the interactions of caffeine with AEDs. For instance, caffeine reduced the protective effects of classic and some newer AEDs against pentylenetetrazol and MESinduced convulsions in mice [3,7,10,29,30]. Noteworthy, the influence of caffeine on the anticonvulsant activity of AEDs against MES-induced seizures was studied after acute and chronic exposures to caffeine. The acute administration of caffeine (in doses of 23.1 and 46.2 mg/kg) reduced the protective effects of the studied AEDs [7,29,30]. Phenobarbital (PB) was the most sensitive to caffeine, and its anticonvulsant activity was reduced in the presence of caffeine given at 11.55 mg/kg. After 15 days of caffeine administration at 23.1 and 46.2 mg/kg (twice daily), the protective effect of phenytoin (PHT) was reduced to a similar degree as in the case of acute caffeine. In contrast, the protection by PB and valproate (VPA) against MES in mice was even more diminished when compared to the acute methylxanthine [29,30]. Strikingly, the anticonvulsant activity of CBZ was not reduced by the acute injection of caffeine and yet, it was considerably diminished following chronic caffeine [29]. Another finding also deserves a special attention. The most pronounced reductions in the anticonvulsant action of AEDs were observed when caffeine was discontinued for 24 h, following its chronic administration, and then a challenge dose of the methylxanthine was given [29,30]. Acute activity of caffeine against the anticonvulsant effects of classic AEDs was also evaluated in the pentylenetetrazol test in mice [31]. Caffeine at 92.4 mg/kg reduced the convulsive threshold for the clonic phase of convulsions in mice and in doses of 69.3 and 92.4 mg/kg attenuated the protective action of ethosuximide, which was reflected by significant increases in the ED50 of this AED to inhibit clonic convulsions. However, even at the dose reducing the threshold of 92.4 mg/kg, caffeine was unable to affect the anticonvulsant action of either clonazepam, PB or VPA. Also, up to 92.4 mg/kg, caffeine did not potentiate the neurotoxic effects (chimney test) of the studied AEDs. In no case, pharmacokinetic mechanism was likely to be involved [31]. One of the newer AEDs, topiramate (TPM), was sensitive to the negative effect of acute caffeine at 23.1 and 46.2 mg/kg -- significant elevations of its ED50 value against MES in mice were observed [32]. Anticonvulsant
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Safety issues in epileptic patients taking AEDs and caffeine or other methylxanthine derivatives
activity of the next newer AED, gabapentin, was reduced by both acute and chronic administrations of caffeine at 46.2 mg/kg [32]. Felbamate seemed more resistant to the untoward action of caffeine. Its anticonvulsant activity was significantly reduced by caffeine only at 161.7 mg/kg [33]. In addition, neither acute nor chronic caffeine affected the protective activity of oxcarbazepine (OXC), lamotrigine (LTG) and tiagabine (TGB) against MES in mice [34]. Also, caffeine, given acutely or chronically, did not modify neurotoxicity of LTG, TGB and OXC, evaluated in the motor coordination test (chimney test). Interestingly, when coadministered with TGB (4 mg/kg), chronic caffeine was found to raise its total plasma concentration [34], pointing to a pharmacokinetic interaction. The influence of caffeine on the protective potency of AEDs has also been studied in rats against MES. When given at a relatively high dose of 200 mg/kg, the methylxanthine reduced the anticonvulsant activity of diazepam, PHT and PB. The anticonvulsant potency of VPA remained unchanged, and the results from the convulsive tests were not pharmacokinetically verified [35]. Clinical data, which show the influence of caffeine on the anticonvulsant activity of AEDs, are rather scant. Anyway, Kaufmann and Sachdeo [36] provide evidence from a patient diagnosed with various types of epilepsy: tonic--clonic, myoclonic, atonic and absence, satisfactorily controlled with two AEDs. There was a sudden increase in seizure frequency because the patient had started to ingest high amounts of caffeine from tea. The seizure frequency quickly returned to baseline when decaffeinated beverages were substituted for tea. Another example describes a patient with symptomatic partial seizures whose, following drinking excessive amounts of coffee, seizure frequency would considerably increase to five simple seizures per day and one complex partial seizure a week [37]. The patient used to drink up to 10 cups of coffee (0.25 l each) daily. The seizure frequency returned to normal upon stopping the habit of drinking coffee [37].
Is blockade of A1 adenosine receptor-mediated events involved in the interaction between AEDs and caffeine?
3.
The experiments clearly demonstrated that caffeine reduce the protective activity of classic and newer AEDs against MES- or pentylenetetrazol-induced convulsions in rodents. Although the threshold for electroconvulsions is unaffected by caffeine [7], the methylxanthine is responsible for the reduction of the convulsive threshold in chemically induced seizures [5,6]. A1 adenosine receptor-mediated events have been postulated to exert a main role in both anticonvulsant effect of adenosine receptor agonists and proconvulsant or convulsant potential of adenosine receptor antagonists [18]. A question arises whether the negative influence of caffeine on the anticonvulsant activity of various AEDs is also due to its blockade of A1 adenosine receptors. This seems unlikely as show experiments
evaluating the effect of the non-xanthine adenosine antagonist, 5-amino-9-chloro-2-(2-furyl)-1,2,4-triazole[1,5-c] quinazoline (CGS 15943A), on the protective activity of classic AEDs against MES in mice [38]. There was no influence of CGS 15943A on the anticonvulsant potency of classic AEDs except for PHT. Consequently, among a number of AEDs whose anticonvulsant potential is reduced by caffeine, only in case of PHT an involvement of A1 adenosine receptors seems probable [38]. Other possible mechanisms of interaction between caffeine and AEDs require a consideration. One possible mechanism may involve the caffeine-dependent release of calcium ions from the endoplasmic reticulum [39,40], an effect mediated by ryanodine receptors [41]. In fact, caffeine has been associated with epileptiform electrical activity in rat hippocampal slices via this mechanism. Clonazepam, CBZ and VPA reduced caffeine-induced epileptiform activity, probably through an interaction with caffeine at ryanodine receptors, clonazepam being the most potent in this respect [39]. The other possible mechanism responsible for the interaction of AEDs with caffeine may be inhibition of phosphodiesterases by the methylxanthine at high doses [42].
Why some AEDs are resistant to the negative impact of caffeine?
4.
An additional question may be posed on why the resistance of some never AEDs to caffeine against MES may be encountered? The AEDs, whose anticonvulsant potency was reduced by caffeine possess a number of mechanisms of action: they are blockers of L-type and T-type calcium channels (CBZ, TPM and VPA) or voltage-dependent sodium channels (CBZ, PHT and VPA), GABA enhancers (VPA, PB, TPM) and AMPA receptor blockers (PB or TPM) [43,44]. Are there any differences in the mechanisms of action of AEDs whose anticonvulsant potential was not affected by caffeine? The answer is positive. Actually, OXC and LTG (AEDs resistant to the negative influence of caffeine) block other types of calcium channels (N, P/Q and R), this particular mechanism being not shared by classic AEDs or TPM [43,44]. Moreover, although VPA (sensitive to caffeine) and TGB (resistant) lead to a substantial rise in synaptic GABA, this effect of TGB is much more potent [44]. However, the interaction between TGB and caffeine is not free from a pharmacokinetic mechanism [34], which may also be responsible for the resistance of TGB. 5.
Theophylline (aminophylline) and AEDs
The behavioral and electrocorticographic seizure effects of methylxanthine derivatives in rats, genetically prone to epilepsy, were compared [45]. The objective of the research was to estimate the correlation between the seizure potential and the molecular structure and the lipophilic nature of the selected xanthines IBMX (3-isobutyl-1-methylxanthine), theophylline (1,3-dimethylxanthine), caffeine (1,3,7-trimethylxanthine),
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etophylline [7-(2-hydroxyethyl)theophylline], diprophylline [7-(2,3-dihydroxy-propyl)theophylline] and doxophylline [7-(1,3-dioxolan-2-ylmethyl)theophylline] [45]. The highest convulsive potency was shared by IBMX, theophylline and caffeine. Some derivatives were without any convulsive potential (enprofylline, diprophylline, doxophylline and etophylline). Analysis of the lipophilic nature did not result in convincing correlations, so it must be different influences upon the adenosine receptor subtypes that matter [45]. Strong seizure propensity of theophylline (or aminophylline which is theophylline2 ethylenediamine) was documented in animal tests [5,8]. A narrow therapeutic window of aminophylline and a possibility of seizures in patients treated for asthma or obstructive pulmonary disease, often unresponsive to treatment and fatal, have also been shown [46,47]. Noteworthy, cases of grand mal seizures were recorded during intensive treatment of asthma and other pulmonary diseases with theophylline in patients without a history of neurologic disorders. However, plasma concentrations of theophylline in these patients, evaluated 1 h since the onset of seizure activity, exceeded the recommended therapeutic level of the methylxanthine [48]. Due to the fact that patients with epilepsy may be also prescribed methylxanthine derivatives for pulmonary reasons, an untoward interaction between AEDs and methylxanthines is of particular importance. Aminophylline at subconvulsive doses of 50 and 100 mg/kg significantly reduced the anticonvulsant activity of a number of classic AEDs, diazepam, PB, PHT and VPA, in the threshold electroconvulsive test in mice, with CBZ being an exception to the rule [49]. Aminophylline at a dose of 25 mg/kg lowered the anticonvulsant efficacy of PB and VPA against MES in mice and at 50 mg/kg that of PHT [50]. Interestingly, 8-(p-sulfophenyl) theophylline (a derivative of theophylline unable to cross the blood--brain barrier), in an equivalent dose, did not affect the protective activity of PHT, PB and VPA, which speaks for the involvement of central effects of aminophylline in the interaction with AEDs [50]. Both acute- and long-term (twice a day for 14 days) aminophylline treatments in a subconvulsive dose of 50 mg/kg or lower distinctly decreased the anticonvulsive potential of classic AEDs (CBZ, PHT, diazepam, PB and VPA) against MES in mice [51-53]. When given acutely at 50 mg/kg, aminophylline reduced the protective activity of all tested AEDs. However, a further significant increase in its negative impact on the anticonvulsant action of all AEDs was noted when the methylxanthine was given chronically [51-53]. Felbamate, on the other hand, showed a partial resistance to the untoward effect of aminophylline, which had to be given in a much higher dose of 100 mg/kg to diminish its anticonvulsant activity against MES in mice [33]. A comparison was made of the proconvulsive activity of two bronchodilating drugs, theophylline and acepifylline, in terms of their antagonistic activity towards diazepam, PHT and CBZ in electroshock model in rats [54]. Diazepam-, 984
PHT- and CBZ-induced protective effects were reduced by aminophylline at 25 mg/kg, while acepifylline remained ineffective in this respect [54]. Moreover, aminophylline was also tried on the anticonvulsant action of the newer AEDs, TPM and gabapentin in MES and the threshold electroconvulsive test in mice, respectively [55,56]. The methylxanthine was given on an acute (up to 100 mg/kg) or chronic base (for 2 weeks). Also, the influence of aminophylline on the neurotoxicity of TPM or gabapentin in the chimney test was assessed after acute and chronic administrations of the methylxanthine. As regards TPM, its anticonvulsant activity against MES was considerably attenuated with both, acute or chronic aminophylline. The negative impact of chronic aminophylline was even more pronounced as the methylxanthine was still able to reduce the anticonvulsant activity of TPM at 25 mg/kg, which was not the case with the acute methylxanthine. Neither acute nor chronic aminophylline affected TPMinduced neurotoxicity in the chimney test. However, TPM elevated the brain concentration of theophylline, following acute or chronic aminophylline administration. The methylxanthine had, however, no effect on the brain concentration of TPM [55]. Gabapentin (at 75 or 100 mg/kg) increased the threshold for electroconvulsions in mice. Aminophylline, both in acute- and long-term experiments, did not weaken the anticonvulsive potential of gabapentin [56]. Also, aminophylline (at 100 mg/kg) did not have any negative impact on the neurotoxic potential of gabapentin [56]. Apart from these two newer AEDs, aminophylline (50 -- 100 mg/kg) was also shown to reduce the protective potential of LTG against MES in mice [56]. Aminophylline was also documented to reverse the protective effects of both D-3-(2-carboxypiperazine-4-ylo)-1-propenylo1phosphonic (D-CCP-ene-, a competitive antagonist NMDA) as well as VPA against MES in mice [57]. Interestingly, it had no influence on the protective action of 1-(4-aminofenyl)-4-methyl-7,8-methyl-enedioxy-5H-2,3 -- benzodiazepine (GYKI 52466 -- an antagonist of non-NMDA receptors) [57]. Interestingly, the protective action of another nonNMDA receptor antagonist, 7-acetyl-5-(4-aminophenyl)-8,9dihydro-8-methyl-7H-1,3-dioxolo-4,5H-2,3-benzodiazepine hydrochloride (LY 300164), was diminished by aminophylline against MES in mice but only at the relatively high dose of 100 mg/kg [58]. Interactions between AEDs and some methylxanthines are shown in Table 1.
6.
May caffeine be anticonvulsant?
The long-term administration of nonselective antagonists of adenosine receptors and theophylline induces anticonvulsive activity in seizures induced by bicuculline, pentylenetetrazol and NMDA [59-61], whereas their acute administration causes proconvulsive effects in chemical seizures and those kindled from amygdala [62,63].
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Safety issues in epileptic patients taking AEDs and caffeine or other methylxanthine derivatives
Table 1. Influence of caffeine or aminophylline (acute and chronic) upon the anticonvulsant activity of selected antiepileptic drugs against maximal electroshock-induced seizures in mice [7,29,30,32-34,51,52,55,56,58].
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Antiepileptic drug
Phenobarbital Phenytoin Carbamazepine Valproate Topiramate Oxcarbazepine Gabapentin Lamotrigine Felbamate
Caffeine (mg/kg)
Aminophylline (mg/kg)
11.55
23.1
46.2
25
50
100
# #(0) 0(#) 0(0) 0(0) NT 0(0) NT NT
# #(0) #(#) #(#) #(#) 0(0) 0(0) 0(0) 0
#(NT) #(#) #(NT) #(#) #(#) (0) #(#) 0(0) 0(NT)z
NT NT NT NT 0(#) NT NT # NT
#(#) #(#) #(#) #(#) #(#) NT 0(0)* # 0
NT NT NT NT #(#) NT 0(0)* NT #(NT)
*This AED was tested against the electroconvulsive threshold test. z Caffeine significantly reduced the anticonvulsant activity of felbamate at 161.7 mg/kg. #: Reduced anticonvulsant activity; NT: Not tested; 0: No effect on anticonvulsant activity; data in parentheses refer to the chronic administration of methylxanthines.
Does selective antagonism at A1 adenosine receptors produce comparable to methylxanthines effects upon the anticonvulsant effects of AEDs?
7.
8-Cyclopenthyl-1,3-dipropylxantine (CPX), a selective A1 adenosine receptor antagonist, was studied upon on the protective effects of CBZ, PB, PHT and VPA against MES in mice, following acute or chronic administration [64]. Acute CPX (10 mg/kg) did not affect the electroconvulsive seizure threshold. However, when given for 2 weeks at 2.5 and 5 mg/kg, it significantly lowered the seizure threshold [64]. Acute CPX (2.5 mg/kg) weakened only the anticonvulsant effect of PB, and at the same dose of 2.5 mg/kg when given chronically, it decreased the protective effects of PB, PHT and VPA, with the exception of CBZ [64]. Pharmacokinetic verifications indicated that the acute interaction of CPX with PB was pharmacodynamic in nature; however, following long-term administration, CPX elevated the brain concentration of both, PB and VPA [64]. These results clearly indicate that CPX shares with caffeine or aminophylline the potential to reduce the anticonvulsant activity of some AEDs, especially on a chronic base. Nevertheless, not all AEDs affected by caffeine or theophylline are affected by CPX. 8.
Conclusion
Many reports provide evidences that theophylline (aminophylline) or caffeine possess a clear-cut convulsive potential and produce seizure activity in experimental animals. Seizure activity was also shown in clinical conditions, and the reported cases of seizures were associated with a theophylline overdose [5-8,46-48]. Considering that methylxanthines may be prescribed in patients with epilepsy for reasons unrelated to epilepsy or may be ingested as coffee or caffeinated soft
drinks, a question emerges whether methylxanthine derivatives could modify the protective activity of AEDs. Generally, a negative impact of methylxanthines upon the anticonvulsant action of classic AEDs was confirmed and even the protective efficacy of some newer AEDs (LTG only negatively affected by aminophylline, TPM) was also reduced by the methylxanthines. Interestingly, when aminophylline or caffeine were given chronically, their impact on the activity of some AEDs was intensified, showing that no tolerance to the negative actions of methylxanthines developed [3,10,29-32,36,37,49-55,58]. Case reports confirm the preclinical data in that seizure frequency was dramatically raised in patients with epilepsy starting to drink huge amounts of coffee or tea [36,37]. This fact may be interpreted in terms of the methylxanthineinduced reduction in the anticonvulsant efficacy of the antiepileptic therapy. Interestingly, seizure frequency returned to baseline when the patients stopped drinking coffee (tea) [36,37]. Although there are data indicating that ingestion of caffeine may be not associated with increased seizure frequency [65], the existing preclinical and clinical evidences seem to indicate that patients with epilepsy should avoid methylxanthine derivatives. 9.
Expert opinion
Although A1 adenosine receptor-mediated events seem to participate in the anticonvulsant effects of a number of adenosine agonists, the involvement of A1 receptors in the mediation of the negative impact of methylxanthines upon the anticonvulsant activity of AEDs seems not probable. Some AEDs (OXC, LTG, TGB) seem resistant to the untoward effects of caffeine, and probably, patients with epilepsy on these AEDs may not be exposed to the hazardous effects of caffeine ingestion. Case reports point to a close relationship between coffee drinking habit and increase in seizure frequency [36,37]. Usually, the patients experiencing an increase in seizure frequency
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were heavy coffee (tea) drinkers and rather not habitual drinkers. Analysis of 174 patients (established epilepsy was found in 63 patients) for the relationship between caffeine intake (habitual or 24 h prior to seizure) and seizure activity revealed that the methylxanthine did not appear as a common seizure precipitant [65]. Results of another study [66] indicate that out of 100 patients with epilepsy, 78 used to drink coffee and 71 reported no association between ingestion of coffee and seizure activity. But the remaining 7, apparently heavy coffee drinkers (4 -- 5 cups of coffee per day), noticed an apparent correlation between seizure frequency and this habit. Quitting the habit reduced their seizure frequency [66]. Although chronic administration of aminophylline or caffeine led to a significant reduction in the anticonvulsant activity of many AEDs [29,30,51-53], chronic methylxanthines were also shown to exert anticonvulsant effects [59-61]. Considering that clinical evaluations carried out on large number of patients [65,66] did not reveal a significant role for caffeine as a seizure precipitant, a possibility arises that habitual coffee drinking may be less hazardous than that observed in accidental heavy coffee drinkers. Such a conclusion was proposed by Samsonsen et al. [65] when discussing their nonsignificant data regarding the impact of caffeine with the data presented in case reports [36,37]. Consequently, patients with epilepsy on AEDs may be advised to avoid methylxanthines as drugs (mainly aminophylline or pentoxifylline) or ingested as coffee or energetic drinks. In fact, the results of a study conducted on six healthy volunteers proved that there was a strong antagonism between intravenous diazepam (15 mg) and intravenous theophylline (2 mg/kg) in terms of vigilance [67]. Last but not least, nicotine has been shown to reduce the anticonvulsant activity of a number of AEDs (CBZ, LTG, PB, PHT, TPM, VPA) against MES in mice [68]. One may thus assume that at least some cases of ‘drug-resistant’ epilepsy may result from the significant reduction in the anticonvulsant efficacy of AEDs dependent upon the combined effects of caffeine and nicotine. Although caffeine was not identified as a trigger factor for
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the development of epilepsy in young women at risk of seizures or epilepsy, smoking might be associated with the higher possibility of seizures [69]. Although there is no doubt on the negative pharmacodynamic interactions of methylxanthines with some AEDs in animal models of epilepsy, an intriguing possibility exists that the negative impact of caffeine in patients with epilepsy might be due to its effect on sleep. In fact, median plasma caffeine concentration was higher in patients with sleep problems [70]. Also, caffeine abstinence was associated with an improved sleep quality [71]. Consequently, a hypothesis may be put forward that at least some of the negative effects of caffeine in patients with epilepsy may result from sleep deprivation, which is a widely accepted seizure precipitant [72]. Last but not least, a question emerges on whether coffee drinking habit may produce pharmacologically active plasma concentrations of caffeine? The median coffee cup is 225 ml (or 7.5 oz). Caffeine content in a cup of drip coffee is from 115 to 175 mg, brewed coffee, from 80 to 135 and instant coffee, from 65 to 100 mg. In 1991, > 50% of the population in the US drank coffee with an average exceeding three cups daily. In the UK, Sweden and Finland, the average intake of coffee is twice as big [73]. No doubt, these data clearly indicate that coffee drinking results in pharmacologically relevant caffeine plasma concentration [9].
Declaration of interest The preparation of this paper was supported by funds from the Medical University of Lublin and Institute of Rural Health in Lublin, Poland. SJ Czuczwar receives an unrestricted grant from GlaxoSmithKline and lectures for GlaxoSmithKline, Janssen, UCB and Sanofi-Aventis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Safety issues in epileptic patients taking AEDs and caffeine or other methylxanthine derivatives
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Affiliation Magdalena Chros´cin´ska-Krawczyk1, Iwona Radzik2, Barbara Miziak2 & Stanisław J Czuczwar†2,3 † Author for correspondence 1 Medical University of Lublin, Department of Pediatrics, Endocrinology and Neurology, Chodzki 2, PL 20-093 Lublin, Poland 2 Medical University, Department of Pathophysiology, Jaczewskiego 8, PL 20-090 Lublin, Poland 3 Institute of Rural Health, Department of Physiopathology, Jaczewskiego 2, PL 20-950 Lublin, Poland Tel: +48 81 718 7365; Fax: +48 81 718 7364; E-mail: [email protected]
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Safety considerations for patients with epilepsy taking antiepileptic drugs alongside caffeine or other methylxanthine derivatives
1.
Introduction
2.
Caffeine and AEDs
3.
Is blockade of A1 adenosine receptor-mediated events
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involved in the interaction
Magdalena Chros´cin´ska-Krawczyk, Iwona Radzik, Barbara Miziak & Stanisław J Czuczwar† †
Medical University, Department of Pathophysiology, Lublin, Poland
between AEDs and caffeine? 4.
Why some AEDs are resistant to the negative impact of caffeine?
5.
Theophylline (aminophylline) and AEDs
6.
May caffeine be anticonvulsant?
7.
Does selective antagonism at A1 adenosine receptors produce comparable to methylxanthines effects upon the anticonvulsant effects of AEDs?
8.
Conclusion
9.
Expert opinion
Introduction: Antiepileptic drugs (AEDs) are widely used for the treatment of epilepsy. However, ~ 30% of patients do not remain seizure free. It is possible that methylxanthine derivatives (e.g., caffeine and theophylline) may partially account for this outcome. Areas covered: Data on the convulsive activity of methylxanthines are reviewed. The negative impact of caffeine and theophylline (or aminophylline) on the protective activity of classic and newer AEDs is also considered. Case report studies indicate that ingestion of caffeine may increase seizure frequency, which returns to baseline when the consumption of coffee or caffeine-rich drinks is terminated. However, the existing data also provide clinical evidence that caffeine may not be a trigger for precipitation of seizure activity and this discrepancy is evaluated. Expert opinion: Experimental data indicate that caffeine and aminophylline both significantly reduce the anticonvulsant activity of a number of AEDs. Clinical data are controversial. Patients with epilepsy should be advised not to take methylxanthine-containing medications. Caffeine consumption, especially accidental and in huge quantities, should be avoided in patients with epilepsy. Keywords: caffeine, drug interactions, epilepsy, methylxanthine Expert Opin. Drug Metab. Toxicol. (2014) 10(7):981-989
1.
Introduction
Caffeine (1,3,7-trimethylxanthine) is the most commonly and widely ingested stimulant. It belongs to the group of purine alkaloids and is found in beverages such as coffee, tea and many soft drinks as well as in chocolate products and desiccated coconut. Caffeine is present in appetite stimulants, analgesics and some antiviral drugs. This methylxanthine is probably the most consumed psychoactive substance in the world. It is estimated that in developed countries 90% of people ingest caffeine on a daily basis [1-4]. History of caffeine is associated with the history of coffee. The name of coffee was derived from the Arabian word ‘gahwa’, which means ‘excising tiredness’. The most dangerous complication of caffeine overdose is seizure activity which is induced in rodents in doses over 400 mg/kg [5-8]. Caffeine is a nonselective antagonist of adenosine receptors [9]. The inhibitory role of adenosine in the control of seizure activity has been well characterized [10,11]. There are four main subtypes of adenosine receptors: A1, A2A, A2B and A3. All these subtypes are coupled to G proteins, and adenosine is their endogenous ligand [12]. The greatest concentrations of A1 receptors are found in the CNS, especially in the hippocampus, human cortex, cerebellum, brain stem and spinal cord [12]. They are also found in many organs and tissues, for example, immune system [13]. The 10.1517/17425255.2014.920822 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
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2.
Article highlights. .
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. . .
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Caffeine is the most ingested stimulant, and aminophylline (and other methylxanthines) may be prescribed to epileptic patients for reasons unrelated to epilepsy. Caffeine and aminophylline reduced the anticonvulsant potential of many antiepileptic drugs in rodents. The most pronounced negative impact of methylxanthines was observed after chronic administration or after a challenging dose of caffeine, following caffeine discontinuation. Case report studies seem to support the experimental results. Other reports, however, do not confirm that caffeine may be a trigger for seizure activity. Probably, accidental ingestion of methylxanthines in high amounts may be more hazardous than habitual ingestion. Considering the results of experimental studies and some clinical data, ingestion of caffeine and curative use of methylxanthines should be limited in epileptic patients.
This box summarizes key points contained in the article.
A1 receptor activation results in sedation, anticonvulsant activity, anxiolytic effects and depression of motor activity. Further, its activation results in an inhibition of adenylyl cyclase causing a decrease in cAMP [14]. The stimulation of A2 receptor activates adenylyl cyclase and results in the release of a number of neurotransmitters: dopamine, norepinephrine, acetylcholine and glutamate [15,16]. The A2A receptors have a high affinity for adenosine and are restricted to the dopaminerich areas of the brain, for example, as the striatum [17]. Generally, A1 adenosine receptor agonists exert anticonvulsant effects in many rodent models of epilepsy [18] and are able to potentiate the anticonvulsant effects of antiepileptic drugs (AEDs) [19]. The existing data reveal that A2a adenosine receptor antagonists or agonists did not significantly modulate amygdala-kindled seizures in rats [20]. In audiogenic seizures in DBA/2 mice, the A2 receptor agonist CGS 21680 suppressed seizure activity [21]. Results reported by Zeraati et al. [22] provide evidence that A2a receptor agonist produced proconvulsive effect, prolonging after discharges in piriform cortex-kindled rats, when administered into the CA1 hippocampal field. Interestingly, A3 adenosine receptors possess much lower affinity towards adenosine when compared with the former receptor subtypes [23]. The A3 adenosine receptor agonist N6-(3-Iodobenzyl)adenosine-5¢-N-methyluronamide (IB-MECA) was anticonvulsant against pentylenetetrazol in mice but no anticonvulsant effect was noted against electroconvulsions in mice [24]. However, stimulation of A3 adenosine receptors was most likely associated with an enhancement of the protective activity of carbamazepine (CBZ) against maximal electroshock (MES)-induced convulsions in mice [25]. 982
Caffeine and AEDs
Caffeine, which is a nonselective antagonist of adenosine receptors, preferably of A1 and A2 [9], has been documented to produce seizures per se [5-7] and exerts proconvulsive effects in vitro [26]. When caffeine was given at 10 -- 20 mg/kg for postnatal days 7 -- 11, it shortened the latency to pentylenetetrazol (40 mg/kg)-induced rhythmic EEG activation. However, some anticonvulsant effects of the methylxanthine were noted when the convulsant was given at 20 mg/kg [27]. The specific epileptogenic effect of caffeine and other methylxanthines is correlated with their affinities to A1 adenosine receptors [28]. Apart from reports indicating the clear-cut convulsive potential of caffeine and other methylxanthines, there are also data available on the interactions of caffeine with AEDs. For instance, caffeine reduced the protective effects of classic and some newer AEDs against pentylenetetrazol and MESinduced convulsions in mice [3,7,10,29,30]. Noteworthy, the influence of caffeine on the anticonvulsant activity of AEDs against MES-induced seizures was studied after acute and chronic exposures to caffeine. The acute administration of caffeine (in doses of 23.1 and 46.2 mg/kg) reduced the protective effects of the studied AEDs [7,29,30]. Phenobarbital (PB) was the most sensitive to caffeine, and its anticonvulsant activity was reduced in the presence of caffeine given at 11.55 mg/kg. After 15 days of caffeine administration at 23.1 and 46.2 mg/kg (twice daily), the protective effect of phenytoin (PHT) was reduced to a similar degree as in the case of acute caffeine. In contrast, the protection by PB and valproate (VPA) against MES in mice was even more diminished when compared to the acute methylxanthine [29,30]. Strikingly, the anticonvulsant activity of CBZ was not reduced by the acute injection of caffeine and yet, it was considerably diminished following chronic caffeine [29]. Another finding also deserves a special attention. The most pronounced reductions in the anticonvulsant action of AEDs were observed when caffeine was discontinued for 24 h, following its chronic administration, and then a challenge dose of the methylxanthine was given [29,30]. Acute activity of caffeine against the anticonvulsant effects of classic AEDs was also evaluated in the pentylenetetrazol test in mice [31]. Caffeine at 92.4 mg/kg reduced the convulsive threshold for the clonic phase of convulsions in mice and in doses of 69.3 and 92.4 mg/kg attenuated the protective action of ethosuximide, which was reflected by significant increases in the ED50 of this AED to inhibit clonic convulsions. However, even at the dose reducing the threshold of 92.4 mg/kg, caffeine was unable to affect the anticonvulsant action of either clonazepam, PB or VPA. Also, up to 92.4 mg/kg, caffeine did not potentiate the neurotoxic effects (chimney test) of the studied AEDs. In no case, pharmacokinetic mechanism was likely to be involved [31]. One of the newer AEDs, topiramate (TPM), was sensitive to the negative effect of acute caffeine at 23.1 and 46.2 mg/kg -- significant elevations of its ED50 value against MES in mice were observed [32]. Anticonvulsant
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Safety issues in epileptic patients taking AEDs and caffeine or other methylxanthine derivatives
activity of the next newer AED, gabapentin, was reduced by both acute and chronic administrations of caffeine at 46.2 mg/kg [32]. Felbamate seemed more resistant to the untoward action of caffeine. Its anticonvulsant activity was significantly reduced by caffeine only at 161.7 mg/kg [33]. In addition, neither acute nor chronic caffeine affected the protective activity of oxcarbazepine (OXC), lamotrigine (LTG) and tiagabine (TGB) against MES in mice [34]. Also, caffeine, given acutely or chronically, did not modify neurotoxicity of LTG, TGB and OXC, evaluated in the motor coordination test (chimney test). Interestingly, when coadministered with TGB (4 mg/kg), chronic caffeine was found to raise its total plasma concentration [34], pointing to a pharmacokinetic interaction. The influence of caffeine on the protective potency of AEDs has also been studied in rats against MES. When given at a relatively high dose of 200 mg/kg, the methylxanthine reduced the anticonvulsant activity of diazepam, PHT and PB. The anticonvulsant potency of VPA remained unchanged, and the results from the convulsive tests were not pharmacokinetically verified [35]. Clinical data, which show the influence of caffeine on the anticonvulsant activity of AEDs, are rather scant. Anyway, Kaufmann and Sachdeo [36] provide evidence from a patient diagnosed with various types of epilepsy: tonic--clonic, myoclonic, atonic and absence, satisfactorily controlled with two AEDs. There was a sudden increase in seizure frequency because the patient had started to ingest high amounts of caffeine from tea. The seizure frequency quickly returned to baseline when decaffeinated beverages were substituted for tea. Another example describes a patient with symptomatic partial seizures whose, following drinking excessive amounts of coffee, seizure frequency would considerably increase to five simple seizures per day and one complex partial seizure a week [37]. The patient used to drink up to 10 cups of coffee (0.25 l each) daily. The seizure frequency returned to normal upon stopping the habit of drinking coffee [37].
Is blockade of A1 adenosine receptor-mediated events involved in the interaction between AEDs and caffeine?
3.
The experiments clearly demonstrated that caffeine reduce the protective activity of classic and newer AEDs against MES- or pentylenetetrazol-induced convulsions in rodents. Although the threshold for electroconvulsions is unaffected by caffeine [7], the methylxanthine is responsible for the reduction of the convulsive threshold in chemically induced seizures [5,6]. A1 adenosine receptor-mediated events have been postulated to exert a main role in both anticonvulsant effect of adenosine receptor agonists and proconvulsant or convulsant potential of adenosine receptor antagonists [18]. A question arises whether the negative influence of caffeine on the anticonvulsant activity of various AEDs is also due to its blockade of A1 adenosine receptors. This seems unlikely as show experiments
evaluating the effect of the non-xanthine adenosine antagonist, 5-amino-9-chloro-2-(2-furyl)-1,2,4-triazole[1,5-c] quinazoline (CGS 15943A), on the protective activity of classic AEDs against MES in mice [38]. There was no influence of CGS 15943A on the anticonvulsant potency of classic AEDs except for PHT. Consequently, among a number of AEDs whose anticonvulsant potential is reduced by caffeine, only in case of PHT an involvement of A1 adenosine receptors seems probable [38]. Other possible mechanisms of interaction between caffeine and AEDs require a consideration. One possible mechanism may involve the caffeine-dependent release of calcium ions from the endoplasmic reticulum [39,40], an effect mediated by ryanodine receptors [41]. In fact, caffeine has been associated with epileptiform electrical activity in rat hippocampal slices via this mechanism. Clonazepam, CBZ and VPA reduced caffeine-induced epileptiform activity, probably through an interaction with caffeine at ryanodine receptors, clonazepam being the most potent in this respect [39]. The other possible mechanism responsible for the interaction of AEDs with caffeine may be inhibition of phosphodiesterases by the methylxanthine at high doses [42].
Why some AEDs are resistant to the negative impact of caffeine?
4.
An additional question may be posed on why the resistance of some never AEDs to caffeine against MES may be encountered? The AEDs, whose anticonvulsant potency was reduced by caffeine possess a number of mechanisms of action: they are blockers of L-type and T-type calcium channels (CBZ, TPM and VPA) or voltage-dependent sodium channels (CBZ, PHT and VPA), GABA enhancers (VPA, PB, TPM) and AMPA receptor blockers (PB or TPM) [43,44]. Are there any differences in the mechanisms of action of AEDs whose anticonvulsant potential was not affected by caffeine? The answer is positive. Actually, OXC and LTG (AEDs resistant to the negative influence of caffeine) block other types of calcium channels (N, P/Q and R), this particular mechanism being not shared by classic AEDs or TPM [43,44]. Moreover, although VPA (sensitive to caffeine) and TGB (resistant) lead to a substantial rise in synaptic GABA, this effect of TGB is much more potent [44]. However, the interaction between TGB and caffeine is not free from a pharmacokinetic mechanism [34], which may also be responsible for the resistance of TGB. 5.
Theophylline (aminophylline) and AEDs
The behavioral and electrocorticographic seizure effects of methylxanthine derivatives in rats, genetically prone to epilepsy, were compared [45]. The objective of the research was to estimate the correlation between the seizure potential and the molecular structure and the lipophilic nature of the selected xanthines IBMX (3-isobutyl-1-methylxanthine), theophylline (1,3-dimethylxanthine), caffeine (1,3,7-trimethylxanthine),
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etophylline [7-(2-hydroxyethyl)theophylline], diprophylline [7-(2,3-dihydroxy-propyl)theophylline] and doxophylline [7-(1,3-dioxolan-2-ylmethyl)theophylline] [45]. The highest convulsive potency was shared by IBMX, theophylline and caffeine. Some derivatives were without any convulsive potential (enprofylline, diprophylline, doxophylline and etophylline). Analysis of the lipophilic nature did not result in convincing correlations, so it must be different influences upon the adenosine receptor subtypes that matter [45]. Strong seizure propensity of theophylline (or aminophylline which is theophylline2 ethylenediamine) was documented in animal tests [5,8]. A narrow therapeutic window of aminophylline and a possibility of seizures in patients treated for asthma or obstructive pulmonary disease, often unresponsive to treatment and fatal, have also been shown [46,47]. Noteworthy, cases of grand mal seizures were recorded during intensive treatment of asthma and other pulmonary diseases with theophylline in patients without a history of neurologic disorders. However, plasma concentrations of theophylline in these patients, evaluated 1 h since the onset of seizure activity, exceeded the recommended therapeutic level of the methylxanthine [48]. Due to the fact that patients with epilepsy may be also prescribed methylxanthine derivatives for pulmonary reasons, an untoward interaction between AEDs and methylxanthines is of particular importance. Aminophylline at subconvulsive doses of 50 and 100 mg/kg significantly reduced the anticonvulsant activity of a number of classic AEDs, diazepam, PB, PHT and VPA, in the threshold electroconvulsive test in mice, with CBZ being an exception to the rule [49]. Aminophylline at a dose of 25 mg/kg lowered the anticonvulsant efficacy of PB and VPA against MES in mice and at 50 mg/kg that of PHT [50]. Interestingly, 8-(p-sulfophenyl) theophylline (a derivative of theophylline unable to cross the blood--brain barrier), in an equivalent dose, did not affect the protective activity of PHT, PB and VPA, which speaks for the involvement of central effects of aminophylline in the interaction with AEDs [50]. Both acute- and long-term (twice a day for 14 days) aminophylline treatments in a subconvulsive dose of 50 mg/kg or lower distinctly decreased the anticonvulsive potential of classic AEDs (CBZ, PHT, diazepam, PB and VPA) against MES in mice [51-53]. When given acutely at 50 mg/kg, aminophylline reduced the protective activity of all tested AEDs. However, a further significant increase in its negative impact on the anticonvulsant action of all AEDs was noted when the methylxanthine was given chronically [51-53]. Felbamate, on the other hand, showed a partial resistance to the untoward effect of aminophylline, which had to be given in a much higher dose of 100 mg/kg to diminish its anticonvulsant activity against MES in mice [33]. A comparison was made of the proconvulsive activity of two bronchodilating drugs, theophylline and acepifylline, in terms of their antagonistic activity towards diazepam, PHT and CBZ in electroshock model in rats [54]. Diazepam-, 984
PHT- and CBZ-induced protective effects were reduced by aminophylline at 25 mg/kg, while acepifylline remained ineffective in this respect [54]. Moreover, aminophylline was also tried on the anticonvulsant action of the newer AEDs, TPM and gabapentin in MES and the threshold electroconvulsive test in mice, respectively [55,56]. The methylxanthine was given on an acute (up to 100 mg/kg) or chronic base (for 2 weeks). Also, the influence of aminophylline on the neurotoxicity of TPM or gabapentin in the chimney test was assessed after acute and chronic administrations of the methylxanthine. As regards TPM, its anticonvulsant activity against MES was considerably attenuated with both, acute or chronic aminophylline. The negative impact of chronic aminophylline was even more pronounced as the methylxanthine was still able to reduce the anticonvulsant activity of TPM at 25 mg/kg, which was not the case with the acute methylxanthine. Neither acute nor chronic aminophylline affected TPMinduced neurotoxicity in the chimney test. However, TPM elevated the brain concentration of theophylline, following acute or chronic aminophylline administration. The methylxanthine had, however, no effect on the brain concentration of TPM [55]. Gabapentin (at 75 or 100 mg/kg) increased the threshold for electroconvulsions in mice. Aminophylline, both in acute- and long-term experiments, did not weaken the anticonvulsive potential of gabapentin [56]. Also, aminophylline (at 100 mg/kg) did not have any negative impact on the neurotoxic potential of gabapentin [56]. Apart from these two newer AEDs, aminophylline (50 -- 100 mg/kg) was also shown to reduce the protective potential of LTG against MES in mice [56]. Aminophylline was also documented to reverse the protective effects of both D-3-(2-carboxypiperazine-4-ylo)-1-propenylo1phosphonic (D-CCP-ene-, a competitive antagonist NMDA) as well as VPA against MES in mice [57]. Interestingly, it had no influence on the protective action of 1-(4-aminofenyl)-4-methyl-7,8-methyl-enedioxy-5H-2,3 -- benzodiazepine (GYKI 52466 -- an antagonist of non-NMDA receptors) [57]. Interestingly, the protective action of another nonNMDA receptor antagonist, 7-acetyl-5-(4-aminophenyl)-8,9dihydro-8-methyl-7H-1,3-dioxolo-4,5H-2,3-benzodiazepine hydrochloride (LY 300164), was diminished by aminophylline against MES in mice but only at the relatively high dose of 100 mg/kg [58]. Interactions between AEDs and some methylxanthines are shown in Table 1.
6.
May caffeine be anticonvulsant?
The long-term administration of nonselective antagonists of adenosine receptors and theophylline induces anticonvulsive activity in seizures induced by bicuculline, pentylenetetrazol and NMDA [59-61], whereas their acute administration causes proconvulsive effects in chemical seizures and those kindled from amygdala [62,63].
Expert Opin. Drug Metab. Toxicol. (2014) 10(7)
Safety issues in epileptic patients taking AEDs and caffeine or other methylxanthine derivatives
Table 1. Influence of caffeine or aminophylline (acute and chronic) upon the anticonvulsant activity of selected antiepileptic drugs against maximal electroshock-induced seizures in mice [7,29,30,32-34,51,52,55,56,58].
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Antiepileptic drug
Phenobarbital Phenytoin Carbamazepine Valproate Topiramate Oxcarbazepine Gabapentin Lamotrigine Felbamate
Caffeine (mg/kg)
Aminophylline (mg/kg)
11.55
23.1
46.2
25
50
100
# #(0) 0(#) 0(0) 0(0) NT 0(0) NT NT
# #(0) #(#) #(#) #(#) 0(0) 0(0) 0(0) 0
#(NT) #(#) #(NT) #(#) #(#) (0) #(#) 0(0) 0(NT)z
NT NT NT NT 0(#) NT NT # NT
#(#) #(#) #(#) #(#) #(#) NT 0(0)* # 0
NT NT NT NT #(#) NT 0(0)* NT #(NT)
*This AED was tested against the electroconvulsive threshold test. z Caffeine significantly reduced the anticonvulsant activity of felbamate at 161.7 mg/kg. #: Reduced anticonvulsant activity; NT: Not tested; 0: No effect on anticonvulsant activity; data in parentheses refer to the chronic administration of methylxanthines.
Does selective antagonism at A1 adenosine receptors produce comparable to methylxanthines effects upon the anticonvulsant effects of AEDs?
7.
8-Cyclopenthyl-1,3-dipropylxantine (CPX), a selective A1 adenosine receptor antagonist, was studied upon on the protective effects of CBZ, PB, PHT and VPA against MES in mice, following acute or chronic administration [64]. Acute CPX (10 mg/kg) did not affect the electroconvulsive seizure threshold. However, when given for 2 weeks at 2.5 and 5 mg/kg, it significantly lowered the seizure threshold [64]. Acute CPX (2.5 mg/kg) weakened only the anticonvulsant effect of PB, and at the same dose of 2.5 mg/kg when given chronically, it decreased the protective effects of PB, PHT and VPA, with the exception of CBZ [64]. Pharmacokinetic verifications indicated that the acute interaction of CPX with PB was pharmacodynamic in nature; however, following long-term administration, CPX elevated the brain concentration of both, PB and VPA [64]. These results clearly indicate that CPX shares with caffeine or aminophylline the potential to reduce the anticonvulsant activity of some AEDs, especially on a chronic base. Nevertheless, not all AEDs affected by caffeine or theophylline are affected by CPX. 8.
Conclusion
Many reports provide evidences that theophylline (aminophylline) or caffeine possess a clear-cut convulsive potential and produce seizure activity in experimental animals. Seizure activity was also shown in clinical conditions, and the reported cases of seizures were associated with a theophylline overdose [5-8,46-48]. Considering that methylxanthines may be prescribed in patients with epilepsy for reasons unrelated to epilepsy or may be ingested as coffee or caffeinated soft
drinks, a question emerges whether methylxanthine derivatives could modify the protective activity of AEDs. Generally, a negative impact of methylxanthines upon the anticonvulsant action of classic AEDs was confirmed and even the protective efficacy of some newer AEDs (LTG only negatively affected by aminophylline, TPM) was also reduced by the methylxanthines. Interestingly, when aminophylline or caffeine were given chronically, their impact on the activity of some AEDs was intensified, showing that no tolerance to the negative actions of methylxanthines developed [3,10,29-32,36,37,49-55,58]. Case reports confirm the preclinical data in that seizure frequency was dramatically raised in patients with epilepsy starting to drink huge amounts of coffee or tea [36,37]. This fact may be interpreted in terms of the methylxanthineinduced reduction in the anticonvulsant efficacy of the antiepileptic therapy. Interestingly, seizure frequency returned to baseline when the patients stopped drinking coffee (tea) [36,37]. Although there are data indicating that ingestion of caffeine may be not associated with increased seizure frequency [65], the existing preclinical and clinical evidences seem to indicate that patients with epilepsy should avoid methylxanthine derivatives. 9.
Expert opinion
Although A1 adenosine receptor-mediated events seem to participate in the anticonvulsant effects of a number of adenosine agonists, the involvement of A1 receptors in the mediation of the negative impact of methylxanthines upon the anticonvulsant activity of AEDs seems not probable. Some AEDs (OXC, LTG, TGB) seem resistant to the untoward effects of caffeine, and probably, patients with epilepsy on these AEDs may not be exposed to the hazardous effects of caffeine ingestion. Case reports point to a close relationship between coffee drinking habit and increase in seizure frequency [36,37]. Usually, the patients experiencing an increase in seizure frequency
Expert Opin. Drug Metab. Toxicol. (2014) 10(7)
985
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M. Chros´cin´ska-Krawczyk et al.
were heavy coffee (tea) drinkers and rather not habitual drinkers. Analysis of 174 patients (established epilepsy was found in 63 patients) for the relationship between caffeine intake (habitual or 24 h prior to seizure) and seizure activity revealed that the methylxanthine did not appear as a common seizure precipitant [65]. Results of another study [66] indicate that out of 100 patients with epilepsy, 78 used to drink coffee and 71 reported no association between ingestion of coffee and seizure activity. But the remaining 7, apparently heavy coffee drinkers (4 -- 5 cups of coffee per day), noticed an apparent correlation between seizure frequency and this habit. Quitting the habit reduced their seizure frequency [66]. Although chronic administration of aminophylline or caffeine led to a significant reduction in the anticonvulsant activity of many AEDs [29,30,51-53], chronic methylxanthines were also shown to exert anticonvulsant effects [59-61]. Considering that clinical evaluations carried out on large number of patients [65,66] did not reveal a significant role for caffeine as a seizure precipitant, a possibility arises that habitual coffee drinking may be less hazardous than that observed in accidental heavy coffee drinkers. Such a conclusion was proposed by Samsonsen et al. [65] when discussing their nonsignificant data regarding the impact of caffeine with the data presented in case reports [36,37]. Consequently, patients with epilepsy on AEDs may be advised to avoid methylxanthines as drugs (mainly aminophylline or pentoxifylline) or ingested as coffee or energetic drinks. In fact, the results of a study conducted on six healthy volunteers proved that there was a strong antagonism between intravenous diazepam (15 mg) and intravenous theophylline (2 mg/kg) in terms of vigilance [67]. Last but not least, nicotine has been shown to reduce the anticonvulsant activity of a number of AEDs (CBZ, LTG, PB, PHT, TPM, VPA) against MES in mice [68]. One may thus assume that at least some cases of ‘drug-resistant’ epilepsy may result from the significant reduction in the anticonvulsant efficacy of AEDs dependent upon the combined effects of caffeine and nicotine. Although caffeine was not identified as a trigger factor for
986
the development of epilepsy in young women at risk of seizures or epilepsy, smoking might be associated with the higher possibility of seizures [69]. Although there is no doubt on the negative pharmacodynamic interactions of methylxanthines with some AEDs in animal models of epilepsy, an intriguing possibility exists that the negative impact of caffeine in patients with epilepsy might be due to its effect on sleep. In fact, median plasma caffeine concentration was higher in patients with sleep problems [70]. Also, caffeine abstinence was associated with an improved sleep quality [71]. Consequently, a hypothesis may be put forward that at least some of the negative effects of caffeine in patients with epilepsy may result from sleep deprivation, which is a widely accepted seizure precipitant [72]. Last but not least, a question emerges on whether coffee drinking habit may produce pharmacologically active plasma concentrations of caffeine? The median coffee cup is 225 ml (or 7.5 oz). Caffeine content in a cup of drip coffee is from 115 to 175 mg, brewed coffee, from 80 to 135 and instant coffee, from 65 to 100 mg. In 1991, > 50% of the population in the US drank coffee with an average exceeding three cups daily. In the UK, Sweden and Finland, the average intake of coffee is twice as big [73]. No doubt, these data clearly indicate that coffee drinking results in pharmacologically relevant caffeine plasma concentration [9].
Declaration of interest The preparation of this paper was supported by funds from the Medical University of Lublin and Institute of Rural Health in Lublin, Poland. SJ Czuczwar receives an unrestricted grant from GlaxoSmithKline and lectures for GlaxoSmithKline, Janssen, UCB and Sanofi-Aventis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Expert Opin. Drug Metab. Toxicol. (2014) 10(7)
Safety issues in epileptic patients taking AEDs and caffeine or other methylxanthine derivatives
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Affiliation Magdalena Chros´cin´ska-Krawczyk1, Iwona Radzik2, Barbara Miziak2 & Stanisław J Czuczwar†2,3 † Author for correspondence 1 Medical University of Lublin, Department of Pediatrics, Endocrinology and Neurology, Chodzki 2, PL 20-093 Lublin, Poland 2 Medical University, Department of Pathophysiology, Jaczewskiego 8, PL 20-090 Lublin, Poland 3 Institute of Rural Health, Department of Physiopathology, Jaczewskiego 2, PL 20-950 Lublin, Poland Tel: +48 81 718 7365; Fax: +48 81 718 7364; E-mail: [email protected]
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