Posts Tagged AEDs

[BLOG POST] Which are the safest epilepsy drugs in pregnancy? – Neurochecklists Updates

Maternal use of antiepileptic agents during pregnancy and major congenital malformations in children

Bromley RL, Weston J, Marson AG.

JAMA 2017; 318:1700-1701.

Abstract

CLINICAL QUESTION:

Is maternal use of antiepileptic drugs during pregnancy associated with major congenital malformations in children?

BOTTOM LINE:

Certain antiepileptic drugs were associated with increased rates of congenital malformations (eg, spina bifida, cardiac anomalies). Lamotrigine (2.31% in 4195 pregnancies) and levetiracetam (1.77% in 817 pregnancies) were associated with the lowest risk and valproate was associated with the highest risk (10.93% in 2565 pregnancies) compared with the offspring of women without epilepsy (2.51% in 2154 pregnancies).

Also see

Weston J, Bromley R, Jackson CF, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev 2016; 11:CD010224.

Both references are cited in the neurochecklist:

Antiepileptic drugs (AEDs): teratogenicity

Abstract link 1

Abstract link 2

Drugs firms ‘creating ills for every pill’. Publik15 on Flickr. https://www.flickr.com/photos/publik15/3415531899

via Which are the safest epilepsy drugs in pregnancy? – Neurochecklists Updates

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[BLOG POST] The 29 proven anti-epilepsy drugs…and their practical checklists

Neurochecklists Updates

Epilepsy is a big problem for Neurology. It is a common, and often life-long, disease. Epilepsy is like the mythical hydra in its diverse manifestations, and in its duplicitous evasion of treatment.

By http://wellcomeimages.org/indexplus/obf_images/5c/4e/30eb7506272a7b448f0f1f22ae63.jpgGallery: http://wellcomeimages.org/indexplus/image/L0011685.html, CC BY 4.0, Link By http://wellcomeimages.org/indexplus/obf_images/5c/4e/30eb7506272a7b448f0f1f22ae63.jpgGallery: http://wellcomeimages.org/indexplus/image/L0011685.html, CC BY 4.0, Link

The pillars of epilepsy treatment are the anti-epileptic drugs (AEDs). It is however a very tricky business to wield these very powerful tools. For example, one epilepsy medication may work wonders for one form of the epilepsy, and make another type much worse.

Cocktail of drugs. Phillppa Willitts on Flikr. https://www.flickr.com/photos/hippie/2563571511 Cocktail of drugs. Phillppa Willitts on Flikr. https://www.flickr.com/photos/hippie/2563571511

Any successful anti-epilepsy regime must therefore be carefully thought through, requiring a strategy that keeps the following key issues in mind all the time:

Mode of action

Indications

Dosing

Side effects

Interaction with other drugs

Teratogencity

With these in mind, neurochecklists explored the difficult terrain, and came up with comprehensive, but concise, checklists for the 29 essential anti-epilepsy drugs. What better way…

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[Abstract] Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy

Abstract

Objective To characterize the magnitude and time course of pregnancy-related clearance changes for different antiepileptic drugs (AEDs): levetiracetam, oxcarbazepine, topiramate, phenytoin, and valproate. A secondary aim was to determine if a decreased AED serum concentration was associated with increased seizure frequency.

 

Methods Women with epilepsy were enrolled preconception or early in pregnancy and prospectively followed throughout pregnancy and the first postpartum year with daily diaries of AED doses, adherence, and seizures. Study visits with AED concentration measurements occurred every 1–3 months. AED clearances in each trimester were compared to nonpregnant baseline using a mixed linear regression model, with adjustments for age, race, and hours postdose. In women on monotherapy, 2-sample t test was used to compare the ratio to target concentrations (RTC) between women with seizure worsening each trimester and those without.

 

Results AED clearances were calculated for levetiracetam (n = 18 pregnancies), oxcarbazepine (n = 4), topiramate (n = 10), valproate (n = 5), and phenytoin (n = 7). Mean maximal clearances were reached for (1) levetiracetam in first trimester (1.71-fold baseline clearance) (p = 0.0001), (2) oxcarbazepine in second trimester (1.63-fold) (p = 0.0001), and (3) topiramate in second trimester (1.39-fold) (p = 0.025). In 15 women on AED monotherapy, increased seizure frequency in the first, second, and all trimesters was associated with a lower RTC (p < 0.05).

 

Conclusion AED clearance significantly changes by the first trimester for levetiracetam and by the second trimester for oxcarbazepine and topiramate. Lower RTC was associated with seizure worsening. Early therapeutic drug monitoring and dose adjustment may be helpful to avoid increased seizure frequency.

 

via Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy | Neurology

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[Abstract] The use of antidepressant drugs in pregnant women with epilepsy: A study from the Australian Pregnancy Register

Summary

Objective

To study interactions between first‐trimester exposure to antidepressant drugs (ADDs) and antiepileptic drugs (AEDs), and a history of clinical depression and/or anxiety, on pregnancy outcomes and seizure control in pregnant women with epilepsy (WWE).

Methods

We examined data from the Australian Pregnancy Register of Antiepileptic Drugs in Pregnancy, collected from 1999 to 2016. The register is an observational, prospective database, from which this study retrospectively analyzed a cohort. Among the AED‐exposed outcomes, comparisons were made among 3 exposure groups: (1) pregnancy outcomes with first‐trimester exposure to ADDs; (2) outcomes with mothers diagnosed with depression and/or anxiety but who were not medicated with an ADD; and (3) those with mothers who were not diagnosed with depression and/or anxiety and were not medicating with ADD. Prevalence data was analyzed using Fisher’s exact test.

Results

A total of 2124 pregnancy outcomes were included in the analysis; 1954 outcomes were exposed to AEDs in utero, whereas 170 were unexposed. Within the group of WWE taking AEDs, there was no significant difference in the prevalence of malformations in infants who were additionally exposed to ADDs (10.2%, 95% confidence interval [CI] 3.9‐16.6), compared to individuals in the non–ADD‐medicated depression and/or anxiety group (7.7%, 95% CI 1.2‐14.2), or those without depression or anxiety (6.9%, 95% CI 5.7‐8.1; = 0.45). The malformation rates in pregnancy outcomes unexposed to AEDs were also similar in the above groups (= 0.27). In WWE medicated with AEDs and ADDs, the frequency of convulsive seizures (= 0.78), or nonconvulsive seizures (= 0.45) throughout pregnancy, did not differ across comparative groups.

Significance

Co‐medicating with ADDs in WWE taking AEDs does not appear to confer a significant added teratogenic risk, and it does not affect seizure control.

 

via The use of antidepressant drugs in pregnant women with epilepsy: A study from the Australian Pregnancy Register – Sivathamboo – – Epilepsia – Wiley Online Library

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[Abstract] Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update

Abstract

Backgrounds:

Antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment. Since 1989, 18 new AEDs have been licensed for clinical use and there are now 27 licensed AEDs in total for the treatment of patients with epilepsy. Furthermore, several AEDs are also used for the management of other medical conditions, e.g., pain and bipolar disorder. This has led to an increasingly widespread application of therapeutic drug monitoring (TDM) of AEDs, making AEDs among the most common medications for which TDM is performed. The aim of this review is to provide an overview of the indications for AED TDM, to provide key information for each individual AED in terms of the drug’s prescribing indications, key pharmacokinetic characteristics, associated drug-drug pharmacokinetic interactions and the value and the intricacies of TDM for each AED. The concept of the reference range is discussed as well as practical issues such as choice of sample types (total vs free concentrations in blood vs saliva) and sample collection and processing.

Methods:

The present review is based on published articles and searches in PubMed and Google Scholar, last searched March in 2018, in addition to references from relevant papers.

Results:

In total, 171 relevant references were identified and used to prepare this review.

Conclusions:

TDM provides a pragmatic approach to epilepsy care in that bespoke dose adjustments are undertaken based on drug concentrations so as to optimize clinical outcome. For the older first generation AEDs (carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone and valproic acid), much data has accumulated in this regard. However, this is occurring increasingly for the new AEDs (brivaracetam, eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, piracetam, pregabalin, rufinamide, stiripentol, sulthiame, tiagabine, topiramate, vigabatrin and zonisamide).

via Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update

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[Abstract] Pharmacotherapy of epilepsy

Pharmacotherapy of epilepsy is usually initiated after two or more unprovoked seizures, a decision that should be made after assessment of the individual risk of further seizures. Antiepileptic drugs (AEDs) are selected based on documented efficacy for the type of seizures, the epilepsy and possible epilepsy syndrome of the patient, taking potential adverse effects and comorbidity into account. For many AEDs, the mechanisms of action are incompletely understood. More than half of patients with newly diagnosed epilepsy achieve sustained seizure freedom with their first or second drug trials. After a prolonged time of seizure freedom discontinuation of therapy may be considered; the risk of relapse after drug withdrawal can be estimated on the basis of a number of clinical factors. The informed patient’s attitude is essential in all therapy decisions. Treatment is still largely symptomatic, but the future may involve a greater degree of disease-modifying precision medicine.

via [Pharmacotherapy of epilepsy]. – Abstract – Europe PMC

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[Slideshow] Comparing the Safety of Antiepilepsy Drugs in Pregnancy

Comparing the Safety of Antiepilepsy Drugs in Pregnancy

Mar 26, 2018

What are the risks of birth defects and perinatal outcomes for infants exposed to various AEDs in utero?

Source: http://www.neurologytimes.com/slideshows/comparing-safety-antiepilepsy-drugs-pregnancy

 

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[WEB SITE] Antiepileptic Drugs – Medscape

Overview

Modern treatment of seizures started in 1850 with the introduction of bromides, which was based on the theory that epilepsy was caused by an excessive sex drive. In 1910, phenobarbital (PHB), which then was used to induce sleep, was found to have antiseizure activity and became the drug of choice for many years. A number of medications similar to PHB were developed, including primidone.

In 1938, Houston Merrit and Tracy Putnam described animal models for screening multiple compounds for antiepileptic activity in the Journal of the American Medical Association. In 1940, phenytoin (PHT) was found to be an effective drug for the treatment of epilepsy, and since then it has become a major first-line antiepileptic drug (AED) in the treatment of partial and secondarily generalized seizures.

In 1968, carbamazepine (CBZ) was approved, initially for the treatment of trigeminal neuralgia; later, in 1974, it was approved for partial seizures. Ethosuximide has been used since 1958 as a first-choice drug for the treatment of absence seizures without generalized tonic-clonic seizures. Valproate (VPA) was licensed in Europe in 1960 and in the United States in 1978, and now is widely available throughout the world. It became the drug of choice in primary generalized epilepsies and in the mid 1990s was approved for treatment of partial seizures.

These anticonvulsants were the mainstays of seizure treatment until the 1990s, when newer AEDs with good efficacy, fewer toxic effects, better tolerability, and no need for blood level monitoring were developed. A study of live-born infants in Denmark found that exposure to the newer-generation AEDs lamotrigine, oxcarbazepine, topiramate, gabapentin, and levetiracetam in the first trimester was not associated with an increased risk in major birth defects. [1]

The new AEDs have been approved in the United States as add-on therapy only, with the exception of topiramate and oxcarbazepine (OXC); lamotrigine (LTG) is approved for conversion to monotherapy. A meta-analysis of 70 randomized clinical trials confirms the clinical impression that efficacy does not significantly differ among AEDs used for refractory partial epilepsy. [2]

Antiepileptic drugs should be used carefully, with consideration of medication interactions and potential side effects. This is particularly important for special populations, such as patients with HIV/AIDS. [3]

For more information, see Epilepsy and Seizures.

Mechanism of Action

It is important to understand the mechanisms of action and the pharmacokinetics of antiepileptic drugs (AEDs) so that these agents can be used effectively in clinical practice, especially in multidrug regimens (see the image below).

Pearls of antiepileptic drug use and management.
Pearls of antiepileptic drug use and management.

Many structures and processes are involved in the development of a seizure, including neurons, ion channels, receptors, glia, and inhibitory and excitatory synapses. The AEDs are designed to modify these processes so as to favor inhibition over excitation and thereby stop or prevent seizure activity (see the image below).

Dynamic target of seizure control in management of epilepsy is achieving balance between factors that influence excitatory postsynaptic potential (EPSP) and those that influence inhibitory postsynaptic potential (IPSP).

The AEDs can be grouped according to their main mechanism of action, although many of them have several actions and others have unknown mechanisms of action. The main groups include sodium channel blockers, calcium current inhibitors, gamma-aminobutyric acid (GABA) enhancers, glutamate blockers, carbonic anhydrase inhibitors, hormones, and drugs with unknown mechanisms of action (see the image below).

Antiepileptic drugs can be grouped according to th
Antiepileptic drugs can be grouped according to their major mechanism of action. Some antiepileptic drugs work by acting on combination of channels or through some unknown mechanism of action.

[…]

For more Visit site —>  Antiepileptic Drugs: Overview, Mechanism of Action, Sodium Channel Blockers

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[WEB SITE] Medication Adherence Key to Epilepsy Treatment

In assessing the effectiveness of prescribed medication there is a strong emphasis on the ability of the patient to adhere to the regime recommended by the clinician. For individuals with epilepsy, adherence to medication is crucial in preventing or minimizing seizures and their cumulative impact on everyday life. Non-adherence to antiepileptic drugs (AEDs) can result in breakthrough seizures many months or years after a previous episode and can have serious repercussions on an individual’s perceived quality of life. Reasons for non-adherence are complex and multilayered. Patients can accidentally fail to adhere through forgetfulness, misunderstanding, or uncertainty about clinician’s recommendations, or intentionally due to their own expectations of treatment, side-effects, and lifestyle choice.

Adherence in epilepsy

Adherence is acting in accordance with advice, recommendations or instruction. Ways that adherence can be optimized;

  1. Educating individuals and their families and carers in understanding of their condition and the rationale of treatment, reducing the stigma associated with the conditions.
  2. Using simple medication regimes.
  3. Positive relationships between healthcare professionals, the individual with epilepsy and their family and /or carers.
  4. Other measures are; manual telephones follow up, home visits, special reminders, regular appointments/ refill reminders.

While failing to adhere to treatment plans can adversely affect individuals with any general medical condition, Non- adherence to anti-epileptic drugs results to increased risk of status epilepticus (prolonged seizures) resulting into brain damage, SUDEP, risk of injuries, increase rates of admission to hospital due prolonged seizures. The consequences of not taking medication can be more immediate with epilepsy.​

Epilepsy as a chronic condition relies heavily on adherence to medical advice in order to maximize an individual’s quality of life by controlling seizures more effectively while avoiding unwanted side-effects. Treatment of those diagnosed with epilepsy the vast majorities are treated with AEDs and approximately 70% can become seizure-free once the most effective regime is followed.

Monotherapy is viewed as the initial and preferential option for treating epilepsy, the choice of drug depending on seizure type and effectiveness of the drug balanced against possible side-effects. It is difficult to find estimates of how many people are on monotherapy or polytherapy at any one point in time.

However, in one of the cases I encountered that of Sarafina Muthoni from Banana, Kiambu County, she was diagnosed with Epilepsy at a very young age in her primary school days. With no history of such a condition in her family, it got everybody thinking what could have gone wrong with their lovely daughter. After days of trying to figure out, the family had to adapt to reality of their daughter living with Epilepsy. She was lucky to have very supportive parents ready to see her through the long journey of treating the condition. The motivation and support from her loved ones to access medication improved her status by far as she continued to adhere to the prescribed treatment. Unfortunately, the support didn’t last long and the burden of continuing with treatment squarely relied on her. This adversely contributed to the beginning of non-adherence to medication for lack of funds to buy drugs. Not only were finances a challenge but also finding a good hospital to comply was a problem.

Muthoni had to live with the sad reality of pain every time she experienced a seizure. Pain which she clearly knew with access to medication the situation could by far be controlled. At the very worse of her situation she found help. Cheshire Disability Services Kenya (CDSK) a Non-Governmental Organization in Kenya whose objective is to empower an inclusive society of persons with disability and develop their full potential to lead a quality life, in partnership with Kenya Association of People with Epilepsy (KAWE) came for Muthonis’ rescue.

Under CDSK’s program to help Epilepsy patients’ access medication and ensure compliance, Muthoni benefited and today she leads a life full of potential and energy as she explores her skills as a beauty and hair stylist.

As we celebrate International Epilepsy Day on Feb 12th 2018, themed on “Life is beautiful”, Muthoni’s story is a highlight of what beauty is all about. Hers’ is just but one of the many inspiring stories to celebrate during this season of Epilepsy Awareness.

Managing Adherence

Adherence to medication regardless of medical condition remains an important problem in treatment. Factors that have been discussed here – side-effects, drug regime, family support, impact on everyday life, relationship with the clinician – are unlikely to be the only predictors of adherence. While adherence to treatment within the context of epilepsy has been the focus of this review, these factors can equally be applied to various chronic conditions.

Assessment of adherence should be a routine part of management of epilepsy. Further recognition and support should be given to patients who have poor seizure control since they are more likely to be more anxious and have unhelpful illness and treatment beliefs.

Finally, patients may be fully aware of the importance of taking AED medication and the benefits gained by altering their lifestyle choices in order to prevent seizures, but will make a decision about the degree to which they follow advice. Patients only have a small amount of time in contact with the clinician in their “patient role”, after which they return to the practicalities of their everyday routine where their adherence fluctuates based on how they feel their medication affects their quality of life.

Strategies to manage adherence originate from different perspectives. While the medical model may advocate less complex drug regimes, the use of measured pill containers, and minimization of side-effects, the psychosocial model analyzes non-adherence in terms of patient attitudes to medication, stigma, family and peer influences, and ability to manage self care. Neither model can adequately improve adherence independently. Perhaps the best approach is to offer a “menu” of adherence-enhancing strategies. However, what is increasingly clear from both models is that total adherence is an unrealistic goal. The emphasis has shifted away from total adherence towards a compromise with both patient and clinician involved in a joint process of treatment negotiation and decision-making in order to achieve the best outcome for the individual.

 

via Medication Adherence Key to Epilepsy Treatment : Evewoman – The Standard

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[WEB SITE] AEDs: Which Work Best as Monotherapy in Epilepsy? – Neurology Times

Which antiepileptic drugs (AEDs) are best as monotherapy? Before the updated Cochrane review, first-line therapy in adults and children with partial onset seizures was with carbamazepine or lamotrigine. And first-line therapy for generalized seizure onset was with sodium valproate.

©Chaikom/ Shutterstock.com

  • 60%-70% of people with epilepsy reach remission from seizures shortly after starting AED treatment. Most are treated with AED monotherapy. The National Institute for Health and Care Excellence (NICE) guidelines in the UK recommend carbamazepine or lamotrigine as first-line-therapy in adults and children with partial onset seizures and sodium valproate as first-line for generalized onset seizures. A 2007 network meta-analysis of AED monotherapy generally agreed with these recommendations.[1]

     

  • The Cochrane Review of AED monotherapy, which updates previous meta-analysis with studies published since 2007, adds levetiracetam and zonisamide.[2]

    ©xpixel/ Shutterstock.com

  • Individual participant data (IPD) approach were used; considered gold standard for time-to-event pooled network meta-analysis. Combined IPD data from 12,391 people in 36 studies and compared 10 AEDS: carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide. ooled data from trials that did head-to-head comparisons were analyzed; a second analysis combined all data from trials to compare drugs that had not been previously compared.

  • For partial seizures, levetiracetam was found to be significantly better than carbamazepine and lamotrigine. Lamotrigine was significantly better than all other AEDs (except levetiracetam). And carbamazepine was significantly better than gabapentin and phenobarbitone. For generalized onset seizures, valproate was significantly better than carbamazepine, topiramate and phenobarbitone. For both partial and generalized onset seizures: phenobarbitone, the earliest licensed treatment, performed worse in terms of treatment failure than all other treatments.

    ©Chaikom/ Shutterstock.com

  • There were few notable differences for partial or generalized seizure types, except fpr 12-month remission: Carbamazepine was significantly better than levetiracetam for partial seizures; and 6-month remission: Sodium valproate was significantly better than lamotrigine for generalized seizures. Regarding time to bot partial and generalized seizures: the oldest AEDs (phenytoin and phenobarbitone) were generally better than newer AEDs. The most commonly reported adverse events across all drugs: drowsiness/fatigue, headache/migraine, GI disturbances, dizziness/faintness, rash/skin disorders.

  • IPD data were available for just 69% of total participants from 47% of eligible trials, leaving out 31% of eligible participants. Methodological inadequacies in some trials could have biased results

  • 1. Phenobarbitone and phenytoin are better for seizure control, but at the expense of earlier treatment failure. 2. Carbamazepine and lamotrigine are suitable as first-line monotherapy for partial onset seizures; levetiracetam may be a suitable alternative. 3. Sodium valproate is suitable as first-line monotherapy for generalized seizures; lamotrigine and levetiracetam may be suitable alternatives, especially for women of child-bearing age given the potential teratogenicity of sodium valproate 4. Zonisamide may effective in partial onset seizures: evidence is limited and more research is needed.

1. Tudur Smith C, Marson AG, Chadwick DW, Williamson PR. Multiple treatment comparisons in epilepsy monotherapy trials. Trials. 2007;5(8):34
2. Nevitt SJ, Sudell M, Weston J, Tudur Smith C, Marson AG. Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data. Cochrane Database of Systematic Reviews. 2017, Issue 6. Art. No. CD011412.

©Chaikom/ Shutterstock.com

Which AEDs work best as monotherapy?

A new Cochrane review scrutinizes the efficacy and tolerability of various agents.

 

via AEDs: Which Work Best as Monotherapy in Epilepsy? | Neurology Times

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