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liveonearth) wrote2008-04-10 09:18 am
liveonearth) wrote2008-04-10 09:18 am
Entry tags:
Siezure Med Mechanisms
ON DRUG MECHANISMS
print chart from this page: http://www.e-epilepsy.org.uk/pages/articles/show_article.cfm?id=127
from Mechanisms of action of anti-epileptic drugs
Andrew Fisher, Matthew C Walker and Norman G Bowery*
Department of Clinical and Experimental Epilepsy, Institute of Neurology, UCL, London, and *Department of Pharmacology, University of Birmingham Medical School, Birmingham
THREE main mechanisms by which current drugs appear to produce their anticonvulsant activity:
1) Modulation of intrinsic membrane conductances, primarily voltage-gated cationic channels
2) Suppression of excitatory amino acid-mediated synaptic transmission
3) Enhancement of GABAergic inhibitory synaptic transmission, via post-synaptic receptor modulation, inhibition of GABA metabolism or blockade of GABA transport.
PARADOXICAL EFFECTS CAUSED BY MANY FACTORS
--effects are very dosage dependent
--affinity and binding strength differ for each drug, so timing matters
--different neurons have different neurotransmitter receptors
--cell maturity and organism maturity affect gates and receptors present
--most research is on animals
--AED = antiepileptic drug
--levetiracetam has a novel mode of action
--in the last 3 decades many anticonvulsants have been suggested but failed in clinical trials
--we still have a poor understanding of the mechanisms of epilepsy and seizure generation
--the precise mechanisms underlying the efficacy of our presently available drugs remain uncertain
--drugs may terminate but not prevent seizures
--all current drugs treat the symptom, seizures, and do not modify the disease process
--http://www.e-epilepsy.org.uk/pages/articles/show_article.cfm?id=111
--AED developed via screening 22,500 compounds in animals, or via serendipity as in the discovery of antiepileptic effects of bromides and phenobarbitone
--design of AED's based on mechanism has not been particularly sucessful "because the synthesised compounds then turn out to have separate mechanisms of action (e.g. gabapentin and lamotrigine), and second, because most of these drugs have proven to be ineffective or have had unacceptable side effects (e.g. NMDA antagonists)"
--AEDs typically have several putative targets, often not possible to discern which are most germane
--may be many complex effects {even when an AED ostensibly has one target (e.g. tiagabine inhibiting GABA uptake)}
The more important targets of AEDs and which drugs affect those targets
RELEVANT TARGETS
--sodium channels
--calcium channels
--GABAergic system
Other putative and potential targets
--potassium channels
--drugs that affect the glutamatergic system
VOLTAGE GATED SODIUM CHANNELS
--the major target for a number of AEDs
--responsible for the rising phase of an AP, critical for AP generation and propagation
--AP = action potential in "excitable" (nerve) cells
--sodium channel exists in three principle conformational states: 1) hyperpolarised (resting, closed) 2) depolarisation opens channel so Na+ can flow through 3) closed, non-conducting and inactivated
--inactivation is removed by hyperpolarisation
--depolarisation results in a transient inward sodium current that rapidly inactivates
--also exists: a slow inactivated state which occurs with sustained depolarisations, and from which the channel recovers at hyperpolarised potentials over a matter of seconds
--sodium channel = a 260-kDa alpha subunit that forms the sodium selective pore
--pore has a ‘hinged lid' which can only close following voltage-dependent activation and inactivates sodium channels
--there are at least ten different sodium channel isoforms
--Five of these isoforms are present in the central nervous system (in the limbic system)
--these isoforms have some functional differences that are of physiological importance
--sodium channel can also be modulated by protein phosphorylation
--Many drugs (incl some anaesthetics and antiarrhythmics) bind preferentially to inactivated sodium channel, which keeps it inactivated longer, slows the axon firing rate
*--Phenytoin, lamotrigine and carbamazepine bind the inactivated Na+ channel
--All bind in the inner pore of the sodium channel
--drug binding is mutually exclusive
--differences in drug interactions with adjacent aa's partly explains drug specific effects
--different kinetics of AED interactions with the Na+ channel: phenytoin binds more potently with a longer time dependence than carbamazepine but carbamazepine binds faster
--phenytoin affects burst behaviour to a greater extent than normal synaptic transmission
--Oxcarbazepine probably has a similar effect to carbamazepine
--Valproate seems to inhibit rapid repetitive firing but acts at a different site from carbamazepine, lamotrigine and phenytoin
--Phenobarbitone and benzodiazepines may inhibit the sodium channel at high concentrations – concentrations that are not usual in clinical practice, but that may be attained during drug loading
--new AEDs, topiramate and zonisamide, have unclear actions on sodium channels
EPILEPSY DRUG RESISTANCE
--epilepsy can be resistant to drugs
--Sodium channels from patients with refractory temporal lobe epilepsy may be selectively resistant to carbamazepine
--there is some evidence of drug resistance being mediated by multidrug resistant proteins that ‘remove' drug from the extracellular fluid and from their site of action
CALCIUM CHANNELS
--putative targets for a large number of AEDs
--importance in mediating antiepileptic effects remains largely unknown
--pore-forming subunit of calcium channels is similar to that of sodium channels
--mechanism of inactivation are similar to that of the sodium channels
--voltage-gated calcium channels in the brain can be subdivided into four main classes, L, P/Q, N and T type channels24.
--L, P/Q and N type channels are high-voltage activated channels that require significant depolarisation prior to activation
--T type channel is low voltage activated, activated at relatively hyperpolarised potentials.
--the L-type channels are mainly expressed post-synaptically and are involved in post-synaptic calcium efflux following neuronal depolarisation
--L-type channels are slowly inactivated thereby permitting sustained calcium entry
--L-type channels can be blocked pharmacologically by dihydropyridines (e.g. nifedipine) and are heavily regulated by protein phosphorylation and by calcium autoregulation
--In certain neuronal subtypes, (particularly in the hippocampus), the calcium-mediated triggering of the after hyperpolarisation is mainly due to its ability to enter the neuron via L-type channels
--The somatic expression of L-type receptors means that they are ideally placed to open during the depolarisation that occurs with an action potential.
--Blockade of L-type calcium channels can give rise to both anticonvulsant and pro-convulsant effects, possibly by inhibiting synaptic potentiation, yet also inhibiting after hyperpolarisation
--L-type antagonists may inhibit epileptogenesis by inhibiting the calcium entry that secondarily activates various genes necessary for the epileptogenic process
--BUT in experimental models of absence epilepsy, L-type calcium antagonists are found to generate pro-convulsant effects
--Some AEDs have been proposed to antagonise L-type calcium channels including carbamazepine, phenytoin, topiramate and phenobarbitone at high, anaesthetic doses.
--inhibiting N and P/Q type channels via G-protein linked receptors retards neurotransmitter release
--N-type antagonists may, in the hippocampus, preferentially inhibit GABA release onto interneurons, and thus could prevent the inhibition of inhibitory neurons
--AEDs proposed to inhibit N-type calcium channels: topiramate , levetiracetam, lamotrigine and phenobarbitone at high doses.
--Lamotrigine may also inhibit P-type channels
--oxcarbazepine displays mild inhibition of L-type channels
--Ethosuximide = anti-absence drug proposed to inhibit T-type calcium channels
--T-type channels can be subdivided into three types, and the expression of these varies between brain regions. The pharmacological sensitivity of T-type calcium currents differs between peripheral neurons, central nervous system, and neuroendocrine cells.
--Phenytoin and the barbiturates inhibit T-type currents in dorsal root ganglion
GABAA and GABAB RECEPTORS
--Gamma amino butyric acid (GABA) is the major inhibitory neurotransmitter in the brain
--formed and degraded in the GABA shunt
--Glutamic acid decarboxylase (GAD) converts glutamate to GABA
--Promotion of GABA synthesis has been proposed to contribute to the action of some AEDs including VALPROATE
--GABA is degraded by GABA transaminase to succinic semialdehyde; alpha-ketoglutarate accepts the amino group in this reaction to become glutamate.
--GABA acts at two receptor types: ionotropic GABAA & metabotropic GABAB receptors.
--GABAA receptors are expressed post-synaptically within the brain
--several allosteric modulators of GABAA receptors: zinc, neurosteroids, benzodiazepines.
--GABAA receptor activation results in the early rapid component of inhibitory transmission and appears to inhibit the transition of inter-ictal to ictal focal activity in the cerebral cortex by restricting the propagation of epileptiform activity through cortical tissue. During focal seizure activity the extracellular concentration of GABA in the surrounding and contralateral cortices is significantly increased which would the support the concept of GABA serving to terminate and limit the spread of seizure activity.
--GABAA receptors are permeable to chloride and, less so, bicarbonate
--effects of GABAA receptor activation on neuronal voltage are dependent on the chloride and bicarbonate concentration gradients across membrane
--extracellular chloride concentration is higher than the intracellular
--GABAA receptor activation results in an influx of chloride and cellular hyperpolarisation
--under certain circumstances GABAA receptors can mediate excitation rather than inhibition
--Drugs that inhibit carbonic anhydrase such as acetazolamide and topiramate reduce the intracellular bicarbonate and thus can reduce depolarising GABA responses
*--Benzodiazepines are specific modulators of GABAA receptors and act at GABAA receptors that contain an alpha1 , alpha2, alpha3 or alpha5 subunit in combination with a gamma subunit65.
--the alpha1 subunit containing receptors seem to have mainly a sedative effect (benzodiazepines)
*--zolpidem has great affinity for GABAA receptors containing the alpha1 subunit has marked sedative effects and weak anticonvulsant efficacy
--More selective ligands could thus result in benzodiazepine agonists that have less sedative effect and greater anticonvulsant potential. The benzodiazepines' main effect is to increase the affinity of GABAA receptors for GABA, and to increase the probability of receptor opening77,78. There has also been the suggestion that benzodiazepines can increase the conductance of high affinity GABAA receptors79.
*--Barbiturates are less selective than benzodiazepines, and potentiate GABAA receptor-mediated currents, mediated by prolonging receptor opening times
--Topiramate can also potentiate GABAA receptors by an unknown mechanism of action81
--neurosteroid levels may explain why seizures occasionally cluster around the time of menstruation
--paradoxical effects at different levels
--another mech: inhibit GABA uptake or inhibit GABA breakdown
--Vigabatrin irreversibly inhibits GABA transaminase
--GABA uptake and GAT expression change during development, and are also regulated by protein kinase C a direct effect of GABA and tyrosine phosphatase
*--GABA transporter inhibitor: nipecotic acid but has poor penetration across BBB thus only effective in animal epilepsy models, if administered intracerebrally
--tiagabine is a GAT-1 specific, non-transportable, lipid soluble GABA uptake inhibitor.
--vigabatrin increases extracellular GABA with two opposing effects: increases tonic inhibition desensitizing synaptic GABAA receptors thus decreasing synaptic inhibition
--tiagabine could in some circumstances enhance seizure activity.
OTHER TARGETS
POTASSIUM CHANNELS
--one of the most diverse groups of ion channels
--There are persistent potassium currents that determine the resting potential of neurons
--there are also a multitude of voltage-gated potassium channels that influence the resting potential and thus the excitability of neurons
--repolarise neurons following action potentials
--the rate of inactivation of potassium channels, which are activated during an action potential, influences the propensity for rapid repetitive firing
--mechanism of fast inactivation depends on an N-terminal structure that, like a ball and chain, occludes the pore
--voltage-gated potassium channels in the brain can be divided into: channels that rapidly activate and inactivate (A type channels), and channels that open upon depolarisation but do not significantly inactivate (delayed rectifier channels). There are also potassium channels that close upon depolarisation but are open at the resting potential (inward rectifying channels); these channels do not inactivate in the same fashion as the other voltage-gated potassium channels, but the channels are rather blocked by internal ions at depolarised potentials.
--some specific potassium channels are inactivated by acetylcholine – M-type channels.
--most drugs have no or poorly characterised effects on potassium channels
*--Phenytoin may selectively block delayed rectifier potassium channel, such an effect may be pro-convulsant
--Retigabine, a putative AED, has as perhaps its main mode of action potentiation of potassium channels
--modulation of potassium channels will be a future target for AED development.
GLUTAMATE AND GLUTAMATE RECEPTORS
--Glutamate is a nonessential amino acid that does not cross the BBB but is readily synthesised
--GABA transaminase contributes to the synthesis of glutamate
--vigabatrin inhibits GABA transaminase & the breakdown of GABA may decrease the synthesis of glutamate
--Glutamate is abundant in brain tissue (mostly intracellular) and is the major CNS excitatory transmitter
--Glutamate is transported into vesicles by a specific vesicular transporter
--exhaustion of vesicular glutamate has been proposed to be a possible mechanism of seizure termination
--Abnormalities of glutamate uptake have been hypothesised to contribute to seizure generation
--drugs that modulate glutamate uptake may have an antiepileptic effect
--glutamate is at higher concentrations intracellular than extracellular in brain
--glia use glutamate
--glutamate acts on 3 types of receptors with different properties
--NMDA receptors are permeable to calcium and sodium ions, bonds with glycine, glutamate, polyamines and zinc
--NMDA receptors may be influenced by the ambient glutamate concentration, can be activated extra-synaptically by glutamate spillover during excessive synaptic activity such as occurs during seizures
--AMPA and kainate receptors
--Kainate receptors, as well as having a post-synaptic role in exciting interneurons and principal cells, are also present pre-synaptically
--there has been a report of a GluR5 specific antagonist with antiepileptic effects in pilocarpine - induced seizures167, yet there is a separate study demonstrating that GluR5 agonists can be antiepileptic
--Metabotropic glutamate receptors
--Presynaptic proteins
September 2005
This article is reproducible for educational purposes
DEPAKOTE
DILANTIN
--SE: rash, tremors, poor equilibrium, exhaustion
TEGRATOL
PHENOBARIBTAL
NEURONTIN?
LYRICA from Pfizer
--additional med to reduce occurence of siezures
--works in about 50%
--used for fibromyalgia, diabetic peripheral neuropathy, postherpetic neuralgia
--FDA was worried about suicidality and Pfizer reports no risk
--http://www.lyrica.com/content/epi_how_lyrica_treats.jsp?setShowOn=../content/epi_about_lyrica.jsp&setShowHighlightOn=../content/epi_how_lyrica_treats.jsp&source=google&HBX_PK=s_epilepsy+medication&HBX_OU=50&o=25229705|193636898|0
KEPPRA from UCB
--=levetiracetam
--side effects in adults: sleepiness, weakness, dizziness, infection
--SE in children: sleepiness, accidental injury, hostility, irritability, weakness
--http://www.keppra.com/pc/about_keppra/what_to_expect.asp?CMP=KNC-GOC0D7R7U9
OTHER TX:
--ketogenic diet
On drug resistance mechanisms: http://cat.inist.fr/?aModele=afficheN&cpsidt=16940116
Drug-resistant epilepsy with uncontrolled severe seizures despite state-of-the-art medical treatment continues to be a major clinical problem for up to one in three patients with epilepsy. Although drug resistance may emerge or remit in the course of epilepsy or its treatment, in most patients, drug resistance seems to be continuous and to occur de novo. Unfortunately, current antiepileptic drugs (AEDs) do not seem to prevent or to reverse drug resistance in most patients, but add-on therapy with novel AEDs is able to exert a modest seizure reduction in as many as 50% of patients in short-term clinical trials, and a few become seizure free during the trial. It is not known why and how epilepsy becomes drug resistant, while other patients with seemingly identical seizure types can achieve seizure control with medication. Several putative mechanisms underlying drug resistance in epilepsy have been identified in recent years. Based on experimental and clinical studies, two major neurobiologic theories have been put forward: (a) removal of AEDs from the epileptogenic tissue through excessive expression of multidrug transporters, and (b) reduced drug-target sensitivity in epileptogenic brain tissue. On the clinical side, genetic and clinical features and structural brain lesions have been associated with drug resistance in epilepsy. In this article, we review the laboratory and clinical evidence to date supporting the drug-transport and the drug-target hypotheses and provide directions for future research, to define more clearly the role of these hypotheses in the clinical spectrum of drug-resistant epilepsy.
print chart from this page: http://www.e-epilepsy.org.uk/pages/articles/show_article.cfm?id=127
from Mechanisms of action of anti-epileptic drugs
Andrew Fisher, Matthew C Walker and Norman G Bowery*
Department of Clinical and Experimental Epilepsy, Institute of Neurology, UCL, London, and *Department of Pharmacology, University of Birmingham Medical School, Birmingham
THREE main mechanisms by which current drugs appear to produce their anticonvulsant activity:
1) Modulation of intrinsic membrane conductances, primarily voltage-gated cationic channels
2) Suppression of excitatory amino acid-mediated synaptic transmission
3) Enhancement of GABAergic inhibitory synaptic transmission, via post-synaptic receptor modulation, inhibition of GABA metabolism or blockade of GABA transport.
PARADOXICAL EFFECTS CAUSED BY MANY FACTORS
--effects are very dosage dependent
--affinity and binding strength differ for each drug, so timing matters
--different neurons have different neurotransmitter receptors
--cell maturity and organism maturity affect gates and receptors present
--most research is on animals
--AED = antiepileptic drug
--levetiracetam has a novel mode of action
--in the last 3 decades many anticonvulsants have been suggested but failed in clinical trials
--we still have a poor understanding of the mechanisms of epilepsy and seizure generation
--the precise mechanisms underlying the efficacy of our presently available drugs remain uncertain
--drugs may terminate but not prevent seizures
--all current drugs treat the symptom, seizures, and do not modify the disease process
--http://www.e-epilepsy.org.uk/pages/articles/show_article.cfm?id=111
--AED developed via screening 22,500 compounds in animals, or via serendipity as in the discovery of antiepileptic effects of bromides and phenobarbitone
--design of AED's based on mechanism has not been particularly sucessful "because the synthesised compounds then turn out to have separate mechanisms of action (e.g. gabapentin and lamotrigine), and second, because most of these drugs have proven to be ineffective or have had unacceptable side effects (e.g. NMDA antagonists)"
--AEDs typically have several putative targets, often not possible to discern which are most germane
--may be many complex effects {even when an AED ostensibly has one target (e.g. tiagabine inhibiting GABA uptake)}
The more important targets of AEDs and which drugs affect those targets
RELEVANT TARGETS
--sodium channels
--calcium channels
--GABAergic system
Other putative and potential targets
--potassium channels
--drugs that affect the glutamatergic system
VOLTAGE GATED SODIUM CHANNELS
--the major target for a number of AEDs
--responsible for the rising phase of an AP, critical for AP generation and propagation
--AP = action potential in "excitable" (nerve) cells
--sodium channel exists in three principle conformational states: 1) hyperpolarised (resting, closed) 2) depolarisation opens channel so Na+ can flow through 3) closed, non-conducting and inactivated
--inactivation is removed by hyperpolarisation
--depolarisation results in a transient inward sodium current that rapidly inactivates
--also exists: a slow inactivated state which occurs with sustained depolarisations, and from which the channel recovers at hyperpolarised potentials over a matter of seconds
--sodium channel = a 260-kDa alpha subunit that forms the sodium selective pore
--pore has a ‘hinged lid' which can only close following voltage-dependent activation and inactivates sodium channels
--there are at least ten different sodium channel isoforms
--Five of these isoforms are present in the central nervous system (in the limbic system)
--these isoforms have some functional differences that are of physiological importance
--sodium channel can also be modulated by protein phosphorylation
--Many drugs (incl some anaesthetics and antiarrhythmics) bind preferentially to inactivated sodium channel, which keeps it inactivated longer, slows the axon firing rate
*--Phenytoin, lamotrigine and carbamazepine bind the inactivated Na+ channel
--All bind in the inner pore of the sodium channel
--drug binding is mutually exclusive
--differences in drug interactions with adjacent aa's partly explains drug specific effects
--different kinetics of AED interactions with the Na+ channel: phenytoin binds more potently with a longer time dependence than carbamazepine but carbamazepine binds faster
--phenytoin affects burst behaviour to a greater extent than normal synaptic transmission
--Oxcarbazepine probably has a similar effect to carbamazepine
--Valproate seems to inhibit rapid repetitive firing but acts at a different site from carbamazepine, lamotrigine and phenytoin
--Phenobarbitone and benzodiazepines may inhibit the sodium channel at high concentrations – concentrations that are not usual in clinical practice, but that may be attained during drug loading
--new AEDs, topiramate and zonisamide, have unclear actions on sodium channels
EPILEPSY DRUG RESISTANCE
--epilepsy can be resistant to drugs
--Sodium channels from patients with refractory temporal lobe epilepsy may be selectively resistant to carbamazepine
--there is some evidence of drug resistance being mediated by multidrug resistant proteins that ‘remove' drug from the extracellular fluid and from their site of action
CALCIUM CHANNELS
--putative targets for a large number of AEDs
--importance in mediating antiepileptic effects remains largely unknown
--pore-forming subunit of calcium channels is similar to that of sodium channels
--mechanism of inactivation are similar to that of the sodium channels
--voltage-gated calcium channels in the brain can be subdivided into four main classes, L, P/Q, N and T type channels24.
--L, P/Q and N type channels are high-voltage activated channels that require significant depolarisation prior to activation
--T type channel is low voltage activated, activated at relatively hyperpolarised potentials.
--the L-type channels are mainly expressed post-synaptically and are involved in post-synaptic calcium efflux following neuronal depolarisation
--L-type channels are slowly inactivated thereby permitting sustained calcium entry
--L-type channels can be blocked pharmacologically by dihydropyridines (e.g. nifedipine) and are heavily regulated by protein phosphorylation and by calcium autoregulation
--In certain neuronal subtypes, (particularly in the hippocampus), the calcium-mediated triggering of the after hyperpolarisation is mainly due to its ability to enter the neuron via L-type channels
--The somatic expression of L-type receptors means that they are ideally placed to open during the depolarisation that occurs with an action potential.
--Blockade of L-type calcium channels can give rise to both anticonvulsant and pro-convulsant effects, possibly by inhibiting synaptic potentiation, yet also inhibiting after hyperpolarisation
--L-type antagonists may inhibit epileptogenesis by inhibiting the calcium entry that secondarily activates various genes necessary for the epileptogenic process
--BUT in experimental models of absence epilepsy, L-type calcium antagonists are found to generate pro-convulsant effects
--Some AEDs have been proposed to antagonise L-type calcium channels including carbamazepine, phenytoin, topiramate and phenobarbitone at high, anaesthetic doses.
--inhibiting N and P/Q type channels via G-protein linked receptors retards neurotransmitter release
--N-type antagonists may, in the hippocampus, preferentially inhibit GABA release onto interneurons, and thus could prevent the inhibition of inhibitory neurons
--AEDs proposed to inhibit N-type calcium channels: topiramate , levetiracetam, lamotrigine and phenobarbitone at high doses.
--Lamotrigine may also inhibit P-type channels
--oxcarbazepine displays mild inhibition of L-type channels
--Ethosuximide = anti-absence drug proposed to inhibit T-type calcium channels
--T-type channels can be subdivided into three types, and the expression of these varies between brain regions. The pharmacological sensitivity of T-type calcium currents differs between peripheral neurons, central nervous system, and neuroendocrine cells.
--Phenytoin and the barbiturates inhibit T-type currents in dorsal root ganglion
GABAA and GABAB RECEPTORS
--Gamma amino butyric acid (GABA) is the major inhibitory neurotransmitter in the brain
--formed and degraded in the GABA shunt
--Glutamic acid decarboxylase (GAD) converts glutamate to GABA
--Promotion of GABA synthesis has been proposed to contribute to the action of some AEDs including VALPROATE
--GABA is degraded by GABA transaminase to succinic semialdehyde; alpha-ketoglutarate accepts the amino group in this reaction to become glutamate.
--GABA acts at two receptor types: ionotropic GABAA & metabotropic GABAB receptors.
--GABAA receptors are expressed post-synaptically within the brain
--several allosteric modulators of GABAA receptors: zinc, neurosteroids, benzodiazepines.
--GABAA receptor activation results in the early rapid component of inhibitory transmission and appears to inhibit the transition of inter-ictal to ictal focal activity in the cerebral cortex by restricting the propagation of epileptiform activity through cortical tissue. During focal seizure activity the extracellular concentration of GABA in the surrounding and contralateral cortices is significantly increased which would the support the concept of GABA serving to terminate and limit the spread of seizure activity.
--GABAA receptors are permeable to chloride and, less so, bicarbonate
--effects of GABAA receptor activation on neuronal voltage are dependent on the chloride and bicarbonate concentration gradients across membrane
--extracellular chloride concentration is higher than the intracellular
--GABAA receptor activation results in an influx of chloride and cellular hyperpolarisation
--under certain circumstances GABAA receptors can mediate excitation rather than inhibition
--Drugs that inhibit carbonic anhydrase such as acetazolamide and topiramate reduce the intracellular bicarbonate and thus can reduce depolarising GABA responses
*--Benzodiazepines are specific modulators of GABAA receptors and act at GABAA receptors that contain an alpha1 , alpha2, alpha3 or alpha5 subunit in combination with a gamma subunit65.
--the alpha1 subunit containing receptors seem to have mainly a sedative effect (benzodiazepines)
*--zolpidem has great affinity for GABAA receptors containing the alpha1 subunit has marked sedative effects and weak anticonvulsant efficacy
--More selective ligands could thus result in benzodiazepine agonists that have less sedative effect and greater anticonvulsant potential. The benzodiazepines' main effect is to increase the affinity of GABAA receptors for GABA, and to increase the probability of receptor opening77,78. There has also been the suggestion that benzodiazepines can increase the conductance of high affinity GABAA receptors79.
*--Barbiturates are less selective than benzodiazepines, and potentiate GABAA receptor-mediated currents, mediated by prolonging receptor opening times
--Topiramate can also potentiate GABAA receptors by an unknown mechanism of action81
--neurosteroid levels may explain why seizures occasionally cluster around the time of menstruation
--paradoxical effects at different levels
--another mech: inhibit GABA uptake or inhibit GABA breakdown
--Vigabatrin irreversibly inhibits GABA transaminase
--GABA uptake and GAT expression change during development, and are also regulated by protein kinase C a direct effect of GABA and tyrosine phosphatase
*--GABA transporter inhibitor: nipecotic acid but has poor penetration across BBB thus only effective in animal epilepsy models, if administered intracerebrally
--tiagabine is a GAT-1 specific, non-transportable, lipid soluble GABA uptake inhibitor.
--vigabatrin increases extracellular GABA with two opposing effects: increases tonic inhibition desensitizing synaptic GABAA receptors thus decreasing synaptic inhibition
--tiagabine could in some circumstances enhance seizure activity.
OTHER TARGETS
POTASSIUM CHANNELS
--one of the most diverse groups of ion channels
--There are persistent potassium currents that determine the resting potential of neurons
--there are also a multitude of voltage-gated potassium channels that influence the resting potential and thus the excitability of neurons
--repolarise neurons following action potentials
--the rate of inactivation of potassium channels, which are activated during an action potential, influences the propensity for rapid repetitive firing
--mechanism of fast inactivation depends on an N-terminal structure that, like a ball and chain, occludes the pore
--voltage-gated potassium channels in the brain can be divided into: channels that rapidly activate and inactivate (A type channels), and channels that open upon depolarisation but do not significantly inactivate (delayed rectifier channels). There are also potassium channels that close upon depolarisation but are open at the resting potential (inward rectifying channels); these channels do not inactivate in the same fashion as the other voltage-gated potassium channels, but the channels are rather blocked by internal ions at depolarised potentials.
--some specific potassium channels are inactivated by acetylcholine – M-type channels.
--most drugs have no or poorly characterised effects on potassium channels
*--Phenytoin may selectively block delayed rectifier potassium channel, such an effect may be pro-convulsant
--Retigabine, a putative AED, has as perhaps its main mode of action potentiation of potassium channels
--modulation of potassium channels will be a future target for AED development.
GLUTAMATE AND GLUTAMATE RECEPTORS
--Glutamate is a nonessential amino acid that does not cross the BBB but is readily synthesised
--GABA transaminase contributes to the synthesis of glutamate
--vigabatrin inhibits GABA transaminase & the breakdown of GABA may decrease the synthesis of glutamate
--Glutamate is abundant in brain tissue (mostly intracellular) and is the major CNS excitatory transmitter
--Glutamate is transported into vesicles by a specific vesicular transporter
--exhaustion of vesicular glutamate has been proposed to be a possible mechanism of seizure termination
--Abnormalities of glutamate uptake have been hypothesised to contribute to seizure generation
--drugs that modulate glutamate uptake may have an antiepileptic effect
--glutamate is at higher concentrations intracellular than extracellular in brain
--glia use glutamate
--glutamate acts on 3 types of receptors with different properties
--NMDA receptors are permeable to calcium and sodium ions, bonds with glycine, glutamate, polyamines and zinc
--NMDA receptors may be influenced by the ambient glutamate concentration, can be activated extra-synaptically by glutamate spillover during excessive synaptic activity such as occurs during seizures
--AMPA and kainate receptors
--Kainate receptors, as well as having a post-synaptic role in exciting interneurons and principal cells, are also present pre-synaptically
--there has been a report of a GluR5 specific antagonist with antiepileptic effects in pilocarpine - induced seizures167, yet there is a separate study demonstrating that GluR5 agonists can be antiepileptic
--Metabotropic glutamate receptors
--Presynaptic proteins
September 2005
This article is reproducible for educational purposes
DEPAKOTE
DILANTIN
--SE: rash, tremors, poor equilibrium, exhaustion
TEGRATOL
PHENOBARIBTAL
NEURONTIN?
LYRICA from Pfizer
--additional med to reduce occurence of siezures
--works in about 50%
--used for fibromyalgia, diabetic peripheral neuropathy, postherpetic neuralgia
--FDA was worried about suicidality and Pfizer reports no risk
--http://www.lyrica.com/content/epi_how_lyrica_treats.jsp?setShowOn=../content/epi_about_lyrica.jsp&setShowHighlightOn=../content/epi_how_lyrica_treats.jsp&source=google&HBX_PK=s_epilepsy+medication&HBX_OU=50&o=25229705|193636898|0
KEPPRA from UCB
--=levetiracetam
--side effects in adults: sleepiness, weakness, dizziness, infection
--SE in children: sleepiness, accidental injury, hostility, irritability, weakness
--http://www.keppra.com/pc/about_keppra/what_to_expect.asp?CMP=KNC-GOC0D7R7U9
OTHER TX:
--ketogenic diet
On drug resistance mechanisms: http://cat.inist.fr/?aModele=afficheN&cpsidt=16940116
Drug-resistant epilepsy with uncontrolled severe seizures despite state-of-the-art medical treatment continues to be a major clinical problem for up to one in three patients with epilepsy. Although drug resistance may emerge or remit in the course of epilepsy or its treatment, in most patients, drug resistance seems to be continuous and to occur de novo. Unfortunately, current antiepileptic drugs (AEDs) do not seem to prevent or to reverse drug resistance in most patients, but add-on therapy with novel AEDs is able to exert a modest seizure reduction in as many as 50% of patients in short-term clinical trials, and a few become seizure free during the trial. It is not known why and how epilepsy becomes drug resistant, while other patients with seemingly identical seizure types can achieve seizure control with medication. Several putative mechanisms underlying drug resistance in epilepsy have been identified in recent years. Based on experimental and clinical studies, two major neurobiologic theories have been put forward: (a) removal of AEDs from the epileptogenic tissue through excessive expression of multidrug transporters, and (b) reduced drug-target sensitivity in epileptogenic brain tissue. On the clinical side, genetic and clinical features and structural brain lesions have been associated with drug resistance in epilepsy. In this article, we review the laboratory and clinical evidence to date supporting the drug-transport and the drug-target hypotheses and provide directions for future research, to define more clearly the role of these hypotheses in the clinical spectrum of drug-resistant epilepsy.