Manuela Contin

Pharmacokinetic interactions between antiepileptic drugs : Clinical considerations

SummaryAntiepileptic drug interactions represent a common clinical problem which has been compounded by the introduction of many new compounds in recent years. Most pharmacokinetic interactions involve the modification of drug metabolism; the propensity of antiepileptic drugs to interact depends on their metabolic characteristics and action on drug metabolic enzymes.Phenobarbital, phenytoin, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP), epoxide hydrolase and uridine diphosphate glucurono-syltransferase (UDPGT) enzyme systems; oxcarbazepine is a weak inducer of CYP enzymes, probably acting on a few specific isoforms only. All stimulate the rate of metabolism and the clearance of the drugs which are catabolised by the induced enzymes.Valproic acid (valproate sodium) inhibits to different extents many hepatic enzyme system activities involved in drug metabolism and is able to significantly displace drugs from plasma albumin. Felbamate is an inhibitor of some specific CYP isoforms and mitochondrial β-oxidation, whereas it is a weak inducer of other enzyme systems.Topiramate is an inducer of specific CYP isoforms and an inhibitor of other isoforms. Ethosuximide, vigabatrin, lamotrigine, gabapentin and possibly zonisamide and tiagabine have no significant effect on hepatic drug metabolism.Apart from vigabatrin and gabapentin, which are mainly eliminated unchanged by the renal route, all other antiepileptic drugs are metabolised wholly or in part by hepatic enzymes and their disposition may be altered by metabolic changes.Some interactions are clinically unremarkable and some need only careful clinical monitoring, but others require prompt dosage adjustment. From a practical point of view, if valproic acid is added to lamotrigine or phenobarbital therapy, or if felbamate is added to phenobarbital, phenytoin or valproic acid therapy, a significant rise in plasma concentrations of the first drug is expected with a corresponding increase in clinical effects. In these cases a concomitant reduction of the dosage of the first drug is recommended to avoid toxicity. Conversely, if a strong inducer is added to carbamazepine, lamotrigine, valproic acid or ethosuximide monotherapy, a significant decrease in their plasma concentrations is expected within days or weeks, with a possible reduction in efficacy. In these cases a dosage increase of the first drug may be required.

Levetiracetam therapeutic monitoring in patients with epilepsy: effect of concomitant antiepileptic drugs.

Background: Lacosamide (LCM) is one of the newer antiepileptic drugs (AEDs) licensed as add-on treatment for partial epilepsy. Data on LCM pharmacokinetics and interactions are limited and partly contradictory. The purpose of this study was to assess the effect of concomitant AED therapy on steady state plasma concentrations of LCM in a population of patients with epilepsy. Methods: Steady state plasma concentrations of LCM were assessed in a cohort of 75 consecutive patients with epilepsy referred to the Laboratory of Clinical Neuropharmacology for AED therapeutic monitoring over 16 months. Plasma LCM concentrations were measured by high-performance liquid chromatography with spectrophotometric detection. Results: Median morning trough plasma concentration-to-weight-adjusted dose ratio of LCM [(mg/L)/(mg/kg/d)] was significantly reduced (0.94 versus 1.35, P < 0.001) in patients treated with LCM plus AED strong inducers of cytochrome P450 metabolism, namely, carbamazepine, phenobarbital, and phenytoin (group A, n = 33), compared with a pool of patients not comedicated with AED strong inducers, predominantly including oxcarbazepine, levetiracetam, lamotrigine, and valproic acid (group B, n = 42). The 2 groups were comparable for age, gender, weight, LCM daily dose, and dosing frequency. LCM plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 75 to 600 mg/d, although, at a given drug dose, a large interpatient variability was observed in matched, plasma drug concentration. Conclusions: Our findings confirm, in a real-patient clinical setting, preliminary evidence from randomized, clinical trials showing that carbamazepine, phenobarbital, or phenytoin significantly reduces the overall systemic exposure to LCM. From a practical point of view, patients on concomitant AED strong inducers may require a 30% higher dose of LCM compared with patients not receiving strongly inducing AED cotherapy, to achieve the same plasma drug concentration.

Cardiovascular autonomic dysfunction in normotensive awake subjects with obstructive sleep apnoea syndrome

Cardiovascular autonomic function in normotensive awake patients with obstructive sleep apnoea syndrome was studied in 21 normotensive (mean age 48 ± 14 years), drug-free men with obstructive sleep apnoea syndrome. Cardiovascular reflex tests with continuous blood pressure monitoring and biochemical indices were performed the morning after a standard polygraphic sleep recording. A group of 20 agematched (mean age 49 ± 19 years) normal subjects was used as controls. The obstructive sleep apnoea syndrome patients showed higher heart rate and noradrenaline plasma levels (p < 0.05) at rest and a higher blood pressure response to head-up tilt (p < 0.01), suggesting sympathetic overactivity. Respiratory arrhythmia, baroreflex sensitivity index and Valsalva ratio were significantly lower in the obstructive sleep apnoea syndrome group (p < 0.01) whereas the decrease in heart rate induced by the cold face test was significantly higher (p < 0.05) showing a blunting of reflexes dependent on baroreceptor or pulmonary afferents with normal or increased cardiac vagal efferent activity. These abnormalities in autonomic regulation may predispose obstructive sleep apnoea syndrome patients to cardiovascular complications like hypertension and cardiac arrhythmias.

Diurnal Fluctuations in Free and Total Steady‐State Plasma Levels of Carbamazepine and Correlation with Intermittent Side Effects

Summary: The relationship between diurnal fluctuations in free (unbound) and total plasma carbamazepine levels and the appearance of intermittent side effects was investigated in nine epileptic patients receiving chronic therapy with carbamazepine, alone or in combination with phenobarbital. On a three‐times‐daily or four‐times‐daily dosing schedule, both total and free carbamazepine levels fluctuated considerably (on an average, 41 and 45%, respectively, around the mean). Side effects (particularly diplopia and nystagmus) were observed in five patients and showed an intermittent pattern in four. Side effects were never found at total carbamazepine levels<34 μmol/L but invariably appeared at levels >38 μmol/L. At levels between 34 and 38 (μmol/L adverse effects were inconsistently observed. The correlation between plasma carbamazepine levels and manifestations of toxicity was slightly stronger when free rather than total levels were considered. Side effects were always apparent at free levels >7.2 μmol/L. These data underline the limitations of relying on a single drug level determination during the monitoring of carbamazepine therapy and emphasize the necessity of carefully adjusting the dosing schedule, to minimize the appearance of intermittent adverse effects.

REM sleep behaviour disorder differentiates pure autonomic failure from multiple system atrophy with autonomic failure

Ten patients with primary autonomic failure, followed up in a prospective clinical and laboratory study, were finally diagnosed as pure autonomic failure or multiple system atrophy with autonomic failure. Polysomnographic studies were performed in all patients. Whereas all four patients with multiple system atrophy complained of sleep related episodes suggesting REM sleep behaviour disorder (RBD) confirmed by polysomnography, RBD remained absent in the remaining six patients with pure autonomic failure. The data indicate that RBD is an important clinical feature, often heralding multiple system atrophy, but which is absent throughout the course of pure autonomic failure; its recognition can thus be useful in the prognostic evaluation of early primary autonomic failure syndromes.

Pharmacokinetics of levodopa.

This paper reviews the clinically relevant determinants of levodopa peripheral pharmacokinetics and main observed changes in the levodopa concentration–effect relationship with Parkinson’s disease (PD) progression. Available clinically practical strategies to optimise levodopa pharmacokinetics and pharmacodynamics are briefly discussed. Levodopa shows particular pharmacokinetics including an extensive presystemic metabolism, overcome by the combined use of extracerebral inhibitors of the enzyme l-amino acid decarboxylase and rapid absorption in the proximal small bowel by a saturable facilitated transport system shared with other large neutral amino acids. Drug transport from plasma to the brain is mediated by the same carriers operating in the intestinal mucosa. The main strategies to assure reproducibility of both intestinal absorption and delivery to the brain, and the clinical effect include standardization of levodopa dosing with respect to meal times and a controlled dietary protein intake. Levodopa plasma half-life is very short, resulting in marked plasma drug concentration fluctuations which are matched, as the disease progresses, to swings in the therapeutic response (“wearing-off” phenomena). “Wearing-off” phenomena can also be associated, at the more advanced disease stages, with a “negative”, both parkinsonism-exacerbating and dyskinetic effect of levodopa at low, subtherapeutic plasma concentrations. Dyskinesias may also be related to high-levodopa, excessive plasma concentrations. Recognition of the different levodopa toxic response patterns can be difficult on a clinical basis alone and simultaneous monitoring of the levodopa concentration–effect relationship may prove useful to disclose the underlying mechanism and in planning the correct management. Clinically practical strategies to optimise levodopa pharmacokinetics, and possibly its therapeutic response, include liquid drug solutions, controlled release formulations and the use of inhibitors of levodopa metabolism. Unfortunately, these attempts have proved so far only partly successful, due to the complex alterations in cerebral levodopa kinetics which accompany the progressive degeneration of the nigrostriatal dopaminergic system in PD patients.

Nocturnal body core temperature falls in Parkinson's disease but not in multiple-system atrophy

To evaluate whether the circadian rhythm of body core temperature (CRT°) can differentiate Multiple‐System Atrophy (MSA) from Idiopathic Parkinsons disease (IPD).

Response to a Standard Oral Levodopa Test in Parkinsonian Patients with and without Motor Fluctuations

The acute dose-response profile of a standard oral levodopa dose was followed, over a maximum 8-h period, in 13 patients with and 10 patients without motor fluctuations using a battery of motor quantitative tests (tapping and walking speed, and multiple choice reaction and movement times). Thirteen age-matched normal controls performed tapping and psychomotor tests, at the same time intervals, over a 4-h period. Tapping test and movement times proved significantly impaired in all patients and were the best indicator of levodopa effect, while walking speed and reaction times were apparently of less value, except in severely affected patients. The duration of the levodopa antiparkinsonian effect differed markedly between the two groups, since fluctuating patients returned to prelevodopa dose values within 4 h (mean +/- SEM: 203 +/- 16 min), while in the stable group motor scores remained significantly higher than baseline values up to at least 7 h postdose. The magnitude of the effect was similar in the two groups, but response was complicated by mild to severe dyskinesias in 9 of 13 fluctuating subjects. The pharmacokinetic parameters of levodopa were almost identical in the two groups. Our data add further weight to the hypothesis that cerebral pharmacokinetic or pharmacodynamic factors are responsible for motor fluctuations. Oral levodopa doses coupled with objective tests of motor performance may prove a practical clinical tool to assess and optimize the relationship between drug dose and therapeutic effect.

Pharmacokinetic optimisation in the treatment of Parkinson's disease

SummaryThe current symptomatic treatment of Parkinson’s disease mainly relies on agents which are able to restore dopaminergic transmission in the nigrostriatal pathway, such as the dopamine precursor levodopa or direct agonists of dopamine receptors. Ancillary strategies include the use of anticholinergic and antiglutamatergic agents or inhibitors of cerebral dopamine catabolism, such as monoamine oxidase type B inhibitors.Levodopa is the most widely used and effective drug. Its peculiar pharmacokinetics are characterised by an extensive presystemic metabolism, overcome by the combined use of extracerebral inhibitors of the enzyme aromatic-aminoacid decarboxylase and rapid absorption in the proximal small bowel by a saturable facilitated transport system shared with other large neutral amino acids. Drug transport from plasma to the brain is mediated by the same carriers operating in the intestinal mucosa. The main strategies to assure reproducibility of both drug intestinal absorption and delivery to the brain and clinical effect include standardisation of levodopa administration with respect to meal times and a controlled dietary protein intake.The levodopa plasma half-life is very short, resulting in marked plasma drug concentration fluctuations which are matched, as the disease progresses, with swings in the therapeutic response (‘wearing-off’ phenomena). ‘Wearing-off’ phenomena can be also associated, at the more advanced disease stages with a ‘negative’, both parkinsonism-exacerbating and dyskinetic effect of levodopa at subtherapeutic plasma concentrations. Dyskinesias may be also related to high-levodopa, excessive plasma concentrations. Recognition of the different levodopa toxic response patterns can be difficult on a clinical basis alone, and simultaneous monitoring of levodopa concentration-effect relationships may prove useful to disclose the underlying mechanism and in planning the correct pharmacokinetic management.Controlled-release levodopa formulations have been developed in an attempt to smooth out fluctuations in plasma profiles and matched therapeutic responses. The delayed levodopa absorption and lower plasma concentrations which characterise controlled-release formulations compared with standard forms must be taken into account when prescribing dosage regimens and can be complicating factors in the management of the advanced disease stages.The pharmacokinetic and pharmacodynamic characterisation of the other anti-parkinsonian agents is hampered by the lack of sensitive and specific analytical methods to measure their very low plasma drug concentrations and by the difficulty in quantitatively assessing overall moderate drug clinical effects. In clinical practice an optimal dosage schedule is still generally found for each patient on an empirical basis.Future strategies should focus on the search for pharmacological agents with a better kinetic profile, particularly a higher and reproducible bioavailability and a predictable relationship between plasma drug concentration and clinical response. Treatments aimed not only at controlling the symptoms, but also at slowing the neurodegenerative process, are currently under intensive investigation.

Autonomic Nervous System Function in Migraine Without Aura

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