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Epilepsy Is A Chronic Neurological Disorder Health Essay

INTRODUCTION

Normal brain activity is promoted by a balance between excitatory and inhibitory neuronal circuits. Seizure activity, denoted by repetitious and synchronous firing of neurones, can occur when equilibrium is disrupted. Two mechanisms which naturally preserve the stability of normal neuronal functioning include surround inhibition (Activating GABAergic neurons) and a refractory period in the readiness of sodium channels to respond to excitatory post-synaptic potentials. The second mechanism acts at a cellular level (through voltage gated channels).

When brain's normal electrical activity is disrupted by overactive electrical discharges, causing temporary communication problem between nerve cells leads to jerking or thrashing one or more part of the body, or experience unusual feelings or sensations.

Treatment:

Stabilize membrane and prevent depolarization by action on ion channels.

Increase GABAergic transmission.

Decrease EAA transmission.

Classification of anti-epileptic drugs by Mechanism of action:

Action on ion channels

Enhance GABA transmission

Inhibit EAA transmission

Na+

Phenytoin

Carbamazepine

Lamotrigine

Topiramate

Valproic Acid

Ca++

Ethosuximide

Valproic Acid

Benzodiazepines

(Diazepam, Clonazepam)

Barbiturates

(Phenobarbital)

Valproic Acid

Gabapentin

Vigabatrin

Topiramate

Felbamate

Felbamate

Topiramate

Na+

For general tonic-clonic and partial seizures

Ca++

For Absence seizures

Most effective in myoclonic but also in tonic-clonic and partial seizures

Clonazepam: For Absence seizures

Many studies investigated the use of anti-epileptic drugs in several neurological diseases other than epilepsy. These neurological disorders involve neuronal excitability through the modulation of ion channels, receptors and intracellular signalling pathways.

Drugs such as Carbamazepine, gabapentin, lamotrigine, and valproate are written by psychiatrists to treat behavioural disorders. There are few randomize trials on behavioural effects of anti-epileptic drugs. However, anti-epileptic drugs are used to treat a wide spectrum of other behavioural disorders ranging from depression to binge eating. Their growing off-label use in psychiatric disorders other than epilepsy is potentially dangerous. In many cases, these drugs are used without clear evidence that they have beneficial effects.

Anti-epileptic drugs like carbamazepine in psychiatric disorders and valproate in headache drove clinical trial to explore the effectiveness of anti-epileptic drugs in a variety of non-epilepsy indications. The interest grew in the use of the newer medications in a host of non-epilepsy indications with approval of anti-epileptic drug in the 1990s. Over the last two decades, evidence has demonstrated the effectiveness and safety of anti-epileptic drugs in many mood disorders, pain syndromes, and headache.

Psychotropic effects of anti-epileptic drugs:

Anti-epileptic drugs

Psychotropic Effects

Barbiturates

Anxiety, Mood stabilizing, Sleep

Carbamazepine

Aggression, Mania, Mood stabilizing

Ethosuximide

Gabapentin

Anxiety, Insomnia, Social Phobia, Mood stabilizing

Lemotrigine

Mania, Mood stabilizing

Levetiracetam

Phenytoine

Mania

Tiagabine

Mania, Mood stabilizing

Topiramate

Binge eating, Mania, Mood stabilizing

Valproate

Agitation, Aggression, Irritability, Mania, Mood stabilizing

Zonisamide

Mania

Valproate

Uses:-

Mania and the prophylaxis of bipolar disorder, especially mixed states and lithium non-responders.

In schizophrenia, as adjuncts to clozapine when the latter causes fits in therapeutic doses.

Prophylaxis of migraine.

Valproate is effective in a proportion of patients with mania, including non-responders to anti-psychotic drugs and lithium. Patients who respond to valproate do not necessarily respond to carbamazepine and vice versa. 59% of patients on valproate improved compared to only 16% of those on placebo. Most of the improvement occurred within 1-4 days of achieving therapeutic levels. Valproate is effective in rapid-cycling mania than patients with mania, and equally effective in the patients with previously judged responders or non-responders to lithium. Subsequent analyses indicate that patients with mixed affective states may benefit more from valproate than from lithium. The place of valproate in routine practice seems likely to be in combination with anti-psychotic drugs in mania, perhaps particularly in patients with a significant mixture of depressive symptoms, and prophylaxis.

Valproate has been studied less conclusively in prophylaxis but it may be used alone or as an adjunct in those who are resistant to lithium or carbamazepine.

Valproic acid is the only anti-epileptic drug approved for migraine prevention, while other newer agents, such as gabapentin and topiramate, are being evaluated. It was approved for migraine prophylaxis by the US food and Drug Administration in 1996 and is used in the form of divalproex, an oligomeric complex composed of valproate sodium and valproic acid in a 1:1 ratio. The mechanism of action of valproic acid in migraine prophylaxis may be related to facilitation of GABAergic neurotransmission and attenuation of neurogenic inflammation suggested by Silberstein SD et al 2002.

Mechanism:-

Valproate is thought to increase the function of the inhibitory transmitter GABA; there is little direct evidence for increase GABA levels but GABA-B receptors may be up-regulated by valproate. The drug may also enhance central serotonin activity, and may reduce adrenocorticotrophic hormone (ACTH) and cortisol levels.

Side-effects:-

Valproate is generally well tolerated, but side-effects include vomiting, tremor, ataxia, weight gain, rash, hair loss.

Carbamazepine

Carbamazepine is dibenzazepine derivatives with a tricyclic structure.

Uses:-

Mania

Trigeminal neuralgia.

The prophylaxis of bipolar disorders

As an adjuncts in depressive illness

For reduction of aggression, an adjunct to anti-psychotic drugs in schizophrenia.

There have been several comparative trials with anti-psychotic drugs or lithium. These suggest that 50-60% patients show a good response to carbamazepine.

Mechanism:-

Carbamazepine reduces L-type calcium channel activation by depolarization, and may block the excitatory transmitter glutamate at NMDA type receptors. It potentiates central 5-HT transmission in normal subjects, as judged by the prolactin response to L-tryptophan.

Side-effects:-

Most side-effects are dose-related and reversible. Treatment should be initiated at low dose and gradually increased to allow tolerance to develop. The use of slow-released preparations, which can be given twice daily, can help to reduce side-effects.

The most common side-effects are nausea, dizziness, ataxia and diplopia. Other common side-effects include headache, drowsiness and nystagmus.

A maculopapular itchy rash develops within 2 weeks in up to 15% of patients, this requires great caution and usually cessation of the drug. This allergic side-effect seems more likely to occur if the dose is raised too quickly.

Serious side-effects are agranulocytosis, aplastic anaemia, and stevens-johnson syndrome. A moderate leucopenia occurs in 1-2% of patients, and often transiently at the start of the treatment. Agranulocytosis and aplastic anaemia can develop suddenly, and occur in about eight patients per million treated.

Lamotrigine

Uses:-

It has anti-depressant effects in both unipolar and bipolar depression. It has proved effective in rapid cycling bipolar-II disorders, perhaps by virtue of anti-depressant effect. Its efficacy in the prophylaxis of bipolar-I disorder is promising, particularly in preventing depression.

In bipolar depression, the double-blind seven week comparison between lamotrigine at 50 or 200mg/day and placebo, in 195 bipolar-I patients experiencing a major depressive episode, showed that depressive symtomatology showed a significant improvement in both 50 and 200mg/day groups by Calabrese JC et al, 1999. In a controlled study of patients with rapid-cycling bipolar disorder, comparison between lamotrigine and placebo during 26-week randomised phase provided evidence that lamotrigine is better than placebo on a number of outcome, in bipolar-II patients. These finding support the efficacy of Lamotrigine in rapid cycling bipolar-II disorder.

Mechanism:-

It blocks fast sodium channels, thereby reducing the size of action potentials in nerve fibres, particularly during repetitive firing. It has also profound effects in reducing calcium currents. These actions are thought to reduce the release of neurotransmitters, especially the excitatory transmitter glutamate.

Side-effects:-

It is generally well tolerated, without weight gain or cognitive impairment. The commonest side-effects are headache, nausea, diplopia, ataxia, and dizziness.

Gabapentin

Gabapentin is an anti drug used for the treatment of epileptic seizures. Gabapentin also provides an analgesic effect which gives rise to its use in the treatment of neuropathic pain. It is structurally related to the neurotransmitter GABA (gamma-amino butyric acid). The actual mechanism of action by which Gabapentin acts in the brain to control seizures and treat pain is not fully understood.

Other recent studies have reported the efficacy of Gabapentin on major depression in unipolar and bipolar-II patients by Kero M et al, 1984. The observation of a specific efficacy in bipolar patients who have co-morbid panic disorder or alcohol abuse appears to be of great importance.

The important pharmacological profile of Gabapentin, in comparison with traditional mood stabilizers, underscores the great tolerability and safety of Gabapentin as an adjunct treatment for thus patients who have partial or no response to standard therapeutic regimens.

Barbiturate

The effects of various barbiturates are generally similar, differing primarily in potency and duration of action. Barbiturates are used clinically for range of indication other than seizure disorders, including the treatment of anxiety, insomnia, and as muscle relaxants and anaesthetic agents. It is responsible for inhibiting K+ channel function leads to increases in neuronal excitability. All barbiturates possess the properties of CNS depressants. Thus, in moderate doses, they produce a drunken euphoric state. Sedation and sleep are produced by increased doses, and higher doses produce surgical anaesthesia.

Side-effects:-

It causes drowsiness and dizziness. Other side-effects may include stomach upset, headache, weakness, grogginess or dreaming.

Phenytoin

It has been used to treat ulcers, epidermolysis bullosa, and inflammatory conditions. It has ability to inhibit collagenase due to its mechanism.

Researchers suggested that phenytoin is effective at cellular level. In some patients, levels of collagenase and epidermolysis increased. Thus phenytoin theoretically stabilizes collagen fibrils and decrease blister formation by Kero M et al, 1984.

Some studied also suggested that phenytoin is also used in treatment of recessive dystrophic epidermolysis bullosa by reducing its blister count suggested by Abahussein AA et al, 1993.

Phenytoin has been studied in the healing of pressure ulcers, venous stasis ulcers, diabetic ulcers, traumatic wounds, and burns by Muthukumarasamy MG et al, 1991. Anstead GM et al, 1996 considered that Phenytoin promotes wound healing through multiple mechanisms which include stimulation of fibroblast proliferation, facilitation of collagen deposition, glucocorticoid antagonism and anti-bacterial activity.

Phenytoin has been used to treat a variety of collagen vascular diseases, genetic, and inflammatory conditions. It has been used in the treatment of discoid lupus erythematosus, but its effects was not confirmed in an evidence-based analysis suggested by Jessop S, 2001 It can be used to treat the painful tonic-dystonic spasms in Sjogren syndrome.

Topiramate

Topiramate is approved in treatment only in seizures. The safety, efficacy and tolerability of Topiramate in treatment of mood disorders, eating disorders are systemic studies and they are underway. The use of topiramate for the control of mood disorders and eating disorders comes mostly from uncontrolled case reports.

McElroy SL et al, 2002 demonstrated that Topiramate is very effective and well tolerated in short term treatment of obesity which is related to binge eating disorders. In study, it had been demonstrated that Topiramate effects significantly highly reduction in binge frequency, binge day frequency, body mass index, and weight than placebo.

Topiramate may represent a valuable alternative to existing mood stabilizers, either as an adjunct or as monotherapy in patients with bipolar or schizoaffective disorders. Preliminary findings provide support for a modest efficacy of topiramate, especially as monotherapy, in the treatment of acute mania by Bozikas VP et al, 2002.

According to Wilding J et al, 2004, the safety and efficacy of topiramate in obese patients have been investigated in randomized, double-blind, placebo-controlled studies. Topiramate clinically significantly decrease weight over one year treatment. Improvements were also observed in blood pressure and glucose tolerance.

Mechanism:-

Topiramate acts on neuronal transmission by following several ways:

By modulating voltage-gated sodium ion channels

Potentiating gamma-aminobutyric acid inhibition

Blocking excitatory glutamate neurotransmission, modulating voltage-gated calcium ion channels, and

By inhibiting carbonic anhydrase, particularly isozymes II and IV.

Side-effects:-

Symptoms of overdose include abdominal pain, agitation, blurred vision, convulsions, depression, dizziness, double vision, drowsiness, impaired coordination, impaired mental activity, low blood pressure, reduced consciousness, severe diarrhoea, sluggishness, and speech problems.

Limitations to the use of Anti-epileptic drugs:-

Adverse effects and drug interactions contribute to treatment failure and reduced quality of life and thus can limit the utility of anti-epileptic drugs in clinical practice.

In general, it can cause adverse effects includes sedation, dizziness, ataxia, fatigue, tremor, dysarthria, paraesthesia, memory impairment, impaired attention, confusion, euphoric mood, irritability, blurred vision and diplopia.

Recently, the FDA reported that there is an increased risk of suicidality in patients taking Anti-epileptic drugs. Previous clinical trial study has found a risk of 0.4% for suicide attempts in patients taking anti-epileptic drugs compared with 0.2% risk in those taking placebo.

Adverse effects can be considered in various categories: They include symptomps of acute toxicity(such as ataxia and blurred vision which occur in association with an excessive dose of carbamazepine, phenytoin or lamotrigine), chronic toxic symptoms includes gingival hyperplasia occuring in about one-third of patients taking phenytoine, where as idiosyncratic reactions includes rash which may be seen with drugs phenytoine, carbamazepin, and lamotrigine. The tolerability of anti-epileptic drugs differs from one drug to another, and the likelihood of appearance of specific adverse effects represents the most important consideration in selecting the drug to be prescribed in the individual patients.

Conclusion

In recent years, the number of commercially available anti-epileptic drugs has increased steadily. Each of the anti-epileptic drugs differs from others in relation to pharmacological properties, efficacy spectrum, side-effect, interaction potential, and cost. Thus, drug treatments with anti-epileptic drugs to the charactristics of the individual patient have never been greater.

In line with the steady improvement in our understanding of the modes of action, efficacy spectrum, and side-effect of anti-epileptic drugs in different patient groups and indications, we can look forward to a more rational use of these agents in the years to come.

In addition to their use for the management of epilepsy, some traditional and newer anti-epileptic drugs may be valuable alternative to standard treatments, in a wide range of non-epileptic neurological and psychiatric conditions, including trigeminal neuralgia, neuropathic pain, migraine prophylaxis, essential tremor and bipolar disorder. Therefore, there is an ongoing need for controlled studies with a large number of patients to improvement in our understanding of the modes of action, efficacy spectrum, and side-effect of anti-epileptic drugs in different patient groups to establish the efficacy of individual anti-epileptic drugs in the management of clinical conditions other than epilepsy.

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