1) Suppress discharge of neurons within a seizure focus; 2) Suppress propagation of seizure activity from the focus to other areas of the brain
5 Basic mechanisms that anti-epileptic drugs act through
Suppression of sodium influx; suppression of calcium influx; promotion of potassium efflux; blockage of receptors for glutamate; and potentiation of gamma-aminobutyric acid (GABA)
Sodium channel physiology
Neuronal action potentials are propagated by influx of sodium through sodium channels, which are gated pores in the cell membrane that control sodium entry; For sodium influx to occur, the channel must be in an activated state; Immediately following sodium entry, the channel goes into an inactivated state, during which further sodium entry is prevented; Under normal circumstances, the inactive channel very quickly returns to the activated state, thereby permitting more sodium entry and propagation of another action potential
Suppression of sodium influx
Several drugs, such as phenytoin, carbamazepine, valproic acid, and lamotrigine, reversibly bind to sodium channels while they are in the inactivated state, and thereby prolong channel inactivation; By delaying return to the active state, these drugs decrease the ability of neurons to fire at high frequency; And as a result, seizures that depend on high-frequency discharge are suppressed
Suppression of calcium influx
Several drugs, such as valproic acid and ethosuximide, block voltage-gated calcium channels; In axon terminals, influx of calcium through voltage-gated calcium channels promotes transmitter release; Hence, drugs that block these calcium channels can suppress transmission
Promotion of potassium efflux
One AED, ezogabine, acts on voltage-gated potassium channels to facilitate potassium efflux; During an action potential, influx of sodium causes neurons to depolarize, and then efflux of potassium causes neurons to repolarize; The action of such as ezogabine is entrusted to slow repetitive neuronal firing and thereby provide seizure control
N-methyl-D-aspartate (NMDA) receptor
Glutamate receptor and ion channel protein found in nerve cells; VERY IMPORTANT for controlling synaptic plasticity and memory function; It is activated when glutamate and glycine (or D-serine) bind to it and when activated, it allows positively charged ions to flow through the cell membrane
Found in many parts of the brain and are most commonly found receptor in the nervous system; It is a non-NMDA-type ionotropic transmembrane receptor for glutamate that medicates fast synaptic transmission in the CNS; Its name is derived from its ability to be activated by the artificial glutamate analog AMPA
Does not bind substrate, yet instead binds another molecule that affects the enzyme’s regulation; When a molecule bind an type of site, it alters alter the enzyme’s shape, or conformation, which then changes how the enzyme functions
Allosteric enzyme regulation
Can activate, or turn on, the enzyme, as well as increase, or turn up, the enzyme’s activity; Can also lower, or turn down, the activity of the enzyme, as well as inactivate, or turn off, the enzyme; Activation state: R or relaxed state where the enzyme is on, and its activity is turned up; T or tense state where the enzyme is off, and its activity is turned down
Antagonism of glutamate
Two drugs, felbamate and topiramate, block the actions of glutamate at N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and thereby suppress neuronal excitation; Glutamic acid (glutamate) is the primary excitatory transmitter in the CNS; The compound works through the two receptors: N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
Gamma-aminobutyric acid (GABA)
An amino acid, which acts as a neurotransmitter in the CNS; It inhibits nerve transmission in the brain, calming nervous activity; And is also directly responsible for the regulation of muscle tone; NOT a alpha amino acid NOR is considered to be incorporated into proteins
Gamma-aminobutyric acid (GABA) actions
In vertebrates, it acts at inhibitory synapses in the brain by binding to specific transmembrane receptors in the plasma membrane of both pre- and post-synaptic neuronal processes. This binding causes the opening of ion channels to allow the flow of either negatively charged chloride ions into the cell or positively charged potassium ions out of the cell. This action results in a negative change in the transmembrane potential, usually causing hyperpolarization
2 general classes of gamma-aminobutyric acid (GABA)
GABAA, which the receptor is part of a ligand-gated ion channel complex; and GABAB metabotropic receptor, which are G-protein coupled receptors that open or close ion channels via intermediaries (G proteins)
Therapeutic uses of gamma-aminobutyric acid (GABA)
Used to relieve anxiety, improve mood, reduce symptoms of premenstrual (PMS), and treat attention deficit-hyperactivity disorder (ADHD); Also used for promoting lean muscle growth, burning fate, stabilizing blood pressure, and relieving pain
Evaluation/Desired outcomes of gamma-aminobutyric (GABA)
Increase sense of well-being, relieving injuries, improving exercise tolerance, decreasing body fat, and increasing lean body weight
Potentiation of Gamma-aminobutyric acid (GABA)
Several AEDs potentiate the action of this, which is an inhibitory neurotransmitter widely distributed throughout the brain; By augmenting the inhibitory influence of this, these drugs decrease neuronal excitability and thereby suppress seizure activity; Drugs increase the influence of this by several mechanisms
Gamma-aminobutyric acid (GABA) drugs
Benzodiazepines and barbiturates enhance the effects of this by mechanisms that involve direct binding to the receptors; Gabapentin promotes this release; Tiagabine inhibits this reuptake, and vigabatrin inhibits the enzyme that degrades this, and thereby increases the availability of this
What is the goal of treating epilepsy?
To reduce seizures to an extent that enables the patient to live a normal or near-normal life
Indicated treatment outcomes for epilepsy
Ideally, should eliminate seizures entirely. However, this may not be possible without causing intolerable side effects. Therefore, a balance of desire for complete seizure control against the acceptability of side effects must be considered
Neurosurgery; Vagus nerve stimulation; and Ketogenic diet
Which non-drug therapy for epilepsy has the best success rate?
Which non-drug therapy for epilepsy is used most widely?
Vagus nerve stimulation
This type of intervention is only cure for epilepsy; For patients with temporal lobe epilepsy; It is only performed on patients who have epilepsy especially hard to treat; Between 5-10 percent of patients experience adverse effects such as infection, visual field defects, memory loss, and paralysis; Prior to this, tests are conducted to locate the seizure focus as well as nearby areas associated with language and other critical functions to enable less removal as possible, minimizing disruption of normal brain function
Vagus nerve stimulation (VNS)
Fighting impulses with impulses; Most widely used non-drug therapy for drug-resistant seizures; Only commercial one available VNS therapy system, which received FDA approval in 1997; Responses to stimulation develop slowly: Initial responses usually occur in 3 months, and full responses take even longer to develop
Vagus nerve stimulation (VNS) Therapy System
Intended for use in conjunction with drugs by patient with severe, uncontrolled seizures; It is a small, programmable pulse generator that is implanted under the collarbone, much like a cardiac pacemaker; Subcutaneous leads connect the generator to the left branch of the vagus nerve in the neck; Stimulation is typically applied for 30 seconds every 5 minutes around the clock; When needed, stimulation parameters (voltage, frequency, duration) can be adjusted externally by the physician
Can and how can patients activate the vagus nerve stimulation (VNS) Therapy System?
Yes; By holding a small magnet over the generator, patients can activate the device manually if they feel a seizure coming on; In addition, patients can use the magnet to turn the generator off
Basic upkeep of the vagus nerve stimulation (VNS) Therapy System
VNS batteries last 3-5 years; Replacement is done in an outpatient procedure that takes 30-60 minutes
Does Not eliminate the need for drugs, yet it can permit a simpler regimen; And although Can reduce the number of type of drugs taken (2 instead of 3)-Does Not permit a reduction in dosage of the drugs that remain
Side effects patients experience during vagus nerve stimulation (VNS) Therapy System
Hoarseness (100 percent), voice alteration (73 percent), coughing (50 percent), and shortness of breath (25 percent). In addition, there is a 2-3 percent risk of infection at the implant site
What does vagus nerve stimulation (VNS) not cause?
Cognitive effects and, perhaps surprisingly, does not cause autonomic effects (e.g., bradycardia, GI disturbances, hypotension)
How does vagus nerve stimulation (VNS) decrease seizure frequency?
No one knows; What is known is that vagal fibers project to the brainstem, and from there to areas of the brain involved in seizure generation; When the vagus is stimulated, the resultant impulses in some way interrupt or prevent abnormal neuronal firing;
In 2005, the vagus nerve stimulation (VNS) Therapy System was also approve for what?
Can decrease seizure frequency, however is hard to implement and potentially dangerous; This is under renewed study as a way to control seizures when drug therapy fails, and even first-line therapy for some patients; Due to being both difficult and hazardous, close medical supervision is essential
2 cornerstones of ketogenic diet
High intake of fat and very low intake of carbohydrates; Fats (usually butter or heavy cream) comprise 80 percent of daily calories, and the remaining 20 percent comprises carbohydrates and proteins
What can develop in just a few day with strict adherence on the ketogenic diet?
Ketosis (not enough carbohydrates from food for cells to burn for energy, reverts to burn fat instead, and makes ketones in process, raising levels of ketone bodies in the body); However, with just a minor deviation from the diet (e.g., ingestion of 2 cookies), ketosis will be lost in hours
How does the ketogenic diet reduce seizures?
The answer is unclear; High intake of fat and low intake of carbohydrates are probably both playing a role in seizure control; However, there is no data showing that ketoacidosis is the reason for seizure control; In fact, another high-fat diet (a modified form of Atkins diet), which does not cause ketoacidosis, can reduce seizure activity
Principle candidates for ketogenic diet
Children under the age of 10 who have not responded to AEDs; About 2/3 of these children respond to the diet, and among the responders, seizure reduction (50 percent) occurs rapidly , typically within a few days
Adverse effects of ketogenic diet
Most consistent and obvious is elevation of blood cholesterol; In one study, cholesterol levels rose from a mean of 170 mg/dL to 245 mg/dL; In another study, 5 children developed sever hyper-cholesterolemia with an average level of 367 mg/dL; Since cholesterol contributes to coronary artery disease (CAD), and since CAD is known to begin early in life, elevation of cholesterol is a significant drawback; Other adverse effects are poor linear growth, poor weight gain, kidney stones, dehydration, acidosis, constipation, and vomiting
*Ketogenic diet and AEDs
Side effects of ketogenic diet are a concern, however AEDs can also cause harm-perhaps even more than the diet. Hence, if the diet allows a reduction in AED use, there may be little or no net increase in harm
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