L16 Epilepsy and anticonvulsants.pdf

Epilepsy and anticonvulsants Peter McNaughton [email protected] Epilepsy and anticonvulsants A description of an epileptic episode Common types of epilepsy Experimental models of epilepsy Antiepileptic drugs The GABAA receptor: actions of barbiturates and benzodiazepines. Use-dependent Na a...

Epilepsy and anticonvulsants Peter McNaughton [email protected] Epilepsy and anticonvulsants A description of an epileptic episode Common types of epilepsy Experimental models of epilepsy Antiepileptic drugs The GABAA receptor: actions of barbiturates and benzodiazepines. Use-dependent Na and Ca ion channel blockers Genetic basis of epilepsy Detailed description of different drug classes and their mechanisms of action Neurophysiology: see Kandel, Schwartz and Jessel, Principles of Neuroscience. Neuropharmacology: see Rang, Dale et al, Pharmacology. http://www.epilepsysociety.org.uk/Forprofessionals/Articles Description of epileptic episodes Video of grand mal seizure Video of partial seizure (Jacksonian epilepsy) Common types of epilepsy Types of epilepsy Generalized seizure (grand mal or tonic-clonic seizure) consists of an initial sustained contracture of the musculature, often accompanied by defecation and cessation of respiration, followed by waves of violent synchronous contraction. Consciousness reappears after several minutes. Generalized seizure (petit mal or absence seizure) not associated with motor function but involves a loss of attention for periods of seconds. Partial seizures (Jacksonian epilepsy) cause muscle spasm in one digit, limb or on one side of the body, often spreading from one location to others. Status epilepticus is when a grand mal seizure continues or repeats for a period of 30 min or more. Life-threatening. EEG The EEG (electroencephalogram) is recorded by attaching electrodes to the scalp. Each action potential or synaptic potential involves a tiny inflow or outflow of membrane current and therefore a small change in extracellular voltage. The electrodes pick up the summed changes in extracellular voltage caused by the activity of many nerve axons and synapses. Examples of seizure activity from EEG recordings Causes of epilepsy Brain injury caused by a stroke or by traumatic injury (car accidents etc) can provide an epileptic focus which persists long after the injury has healed Infection (viral or bacterial) can cause inflammation which provides an epileptic focus Tumours Autoimmune disease can also cause localized encephalitis which provides an epileptic focus Idiopathic: no obvious pathology. By far the commonest type. Experimental models: kindling Uses repetitive electrical or chemical stimulation of a small region of the brain. Initially the stimulation excites only a local brain area. However, after a number of repetitions of stimulation the excitability spreads across the brain in a manner similar to the patterns observed during an epileptic seizure. The phenomenon of kindling has been a very useful experimental tool for developing and testing anti-epileptic drugs Antiepileptic drugs Anti-epileptic drugs There are 2 main classes of anti-epileptic drugs, both of which act to suppress the excitability of neurons: - drugs that act to enhance the activity of inhibitory ion channels gated by the neurotransmitter GABA. Includes barbiturates and benzodiazepines, valproic acid and KBr. - drugs that act to block voltage-dependent Na or Ca channels in a use-dependent manner and so block repetitive nerve activity. They have much less effect on normal action potentials which are not typically elicited with high frequency. Includes phenytoin, carbamazepine, gabapentin. In addition a number of drugs act by other mechanisms, or their mechanisms of action are not well understood. Drugs that enhance opening of the GABAA receptor GABA and inhibition The neurotransmitter GABA is g-amino butyric acid: GABA is the predominant inhibitory neurotransmitter, accounting for some 30% of all synapses in the brain. It is found across most regions of the brain and acts on 3 different types of GABA receptors, GABAA, GABAB and GABAC. The GABAA receptor is a chloride channel. The GABAB receptor is a G-protein coupled receptor (GPCR). It is predominantly presynaptic and acts through Gi to inhibit cAMP production which in turn leads to an enhanced K+ conductance and stabilization of the membrane potential. Agonist baclofen. GABAC receptors are also chloride channels but have a very different subunit composition to GABAA receptors. Benzodiazepines enhance membrane currents induced by GABA The benzodiazepine increases current evoked by GABA. Note that it has no effect when GABA is absent. Binding sites on the GABAA receptor Structure of the GABAA receptor 5 different subunits (a, b, g, d, r) that form a pentameric Clchannel. All of the subunits are able to bind GABA Expression of a, b subunits gives a channel that binds GABA and benzodiazepines with low affinity Expression of a, b and g subunits gives a channel with a pharmacological profile and affinity similar to that of native GABAA receptors in terms of benzodiazepine binding Minimal native channel probably 2 a, 2 b, 1 g. Subunit substitutions with d and r would give further diversity. Each subunit has a range of different isoforms. At present there are 6 known a subunits, 4 b, 3 g, 1 d, 1 r. The potential number of channel permutations from this range of subunits is well into the hundreds. Benzodiazepines Bind to the extracellular domain of a subunits. Promote an increase in affinity of GABA for its binding site. Applied in absence of GABA benzodiazepines have no effect. The different a subunits in the GABAA receptor are expressed in different brain regions, and each a subunit may therefore have a distinct cognitive effect. So far we know that Activating the a1 subunit BZD site has sedative effects. Drugs such as zolpidem (“Z-drugs”, have replaced benzodiazepines as sedatives) are a1-selective. Activating the a2 subunit BZ site has anxiolytic effects - Knocking out the a5 receptor improves cognitive function. Thus activation of the a5 BZ site is probably responsible for the loss of cognitive function caused by benzodiazepines Barbiturates Prolong the open time of the GABAA ion channel. Bind to different site from benzodiazepines. At high enough concentrations barbiturates open the GABAA ion channel even in the absence of GABA. Barbiturates have an allosteric interaction with the GABA binding site and binding of either GABA or barbiturates enhances the binding of the other. There are two major problems with their use: 1. low therapeutic index combined with ability to act in the absence of GABA means that an overdose can be fatal 2. tolerance through up-regulation of P450 enzymes in the liver. Other pharmacological sites on the GABAA receptor Neurosteroid binding site - binding site of the steroidal anaesthetics alphaxalone and propofol. These cause anaesthesia but are not used for epilepsy as they impair normal function. Picrotoxin acts to block the Cl- conductance pore. Thus picrotoxin promotes seizures. Ethanol also enhances GABA action – probably explains the sedative effects of alcohol. Bromide ions (Br-) are more permeable through the GABAA ion channel than Cl- and so enhance inhibition. Bromide was used as a sedative and was the first successful anti-epileptic. No longer used in humans because of toxicity (but used in dogs). Common anti-epileptics acting at the GABAA receptor Diazepam (Valium, a benzodiazepine) is effective in enhancing the effects of endogenous GABA. Widely used as a sedative and anticonvulsant (i.e. anti-epileptic). Midazolam (benzodiazepine) is 2-3 times more potent than diazepam and is used as a sedative and anti-epileptic. Phenobarbital (barbiturate) opens the GABA receptor, even in the absence of endogenous GABA. Effective anticonvulsant but overdose can be fatal (unlike benzodiazepines). Suicide risk – not often used in humans. Use-dependent Na and Ca channel blockers Use-dependent Na and Ca channel blockers +50 mV Na chans open Use-dependent blockers of sodium channels bind only to inactivated Na channels. Thus the more often the channel opens the more potently it is blocked. 0 mV -50 mV Na chans closed Na chans inactivated -100 mV 0 ms 5 ms 10 ms Use-dependent Na and Ca channel blockers - - + Closed Open Inactivated Use-dependent blockers like carbamazepine and phenytoin bind to and prolong the inactivated state So the more often the channel opens, the longer the channel is in the inactivated state and therefore the greater the potency of the blocker. Thus a channel that opens very frequently, because of the rapid firing of action potentials in epilepsy, will be preferentially blocked. Use-dependent Na channel blockers before drug applied after washing Use-dependent block when drug is applied to mouse spinal cord neurones (in culture). Use-dependent block is less when the channel is removed from the inactivated state by hyperpolarization. (A) Oxcarbazepine and (B) its monohydroxy derivative. See Wamil et al., (1994). Eur J Pharmacology 27, 301-308. Summary: effect of a use-dependent Na or Ca channel blocker on firing rate control frequency of firing + drug stimulus Genetic basis of epilepsy Monogenic (single-gene) epilepsy Sometimes inherited (runs in families) More commonly a spontaneous mutation with no familial history Monogenic epilepsy is typically associated with other major signs e.g. developmental delay, visible abnormalities, cognitive and motor impairment Example: Angelman syndrome (“happy puppet syndrome”) Monogenic epilepsy is relatively uncommon Most idiopathic epilepsies (those with no obvious cause) are thought to be polygenic in nature Examples of monogenic epilepsy: GABA GABAA mutations in various subunits (a, b, g etc) ® loss of inhibition ® epilepsy GABAB mutations (rare) GABA-T (GABA transaminase) and SSADH mutations cause epilepsy fits, which seems contradictory as reduced recycling of GABA should increase GABA in the synaptic cleft. May be because these mutations cause extensive CNS abnormalities. Examples of monogenic epilepsy: Na channels Na channel NaV1.1 mainly expressed in inhibitory neurons Loss of function mutations in NaV1.1 cause Dravet syndrome (“severe myoclonic epilepsy of infancy”) Na channel use-dependent blockers (e.g. carbamazepine, phenytoin) worsen the condition Na channels NaV1.2 and NaV1.6 mainly expressed in excitatory neurons Gain of function mutations in NaV1.2 or NaV1.6 cause epileptic fits starting soon after birth Na channel use-dependent blockers are effective treatments Examples of monogenic epilepsy: K channels Large number (around 80) different K channels – cause hyperpolarisation and so stabilise the neuronal membrane potential Perhaps unsurprisingly, loss-of function K channel mutations can cause epilepsy Examples of monogenic epilepsy: other causes Mutations in genes in the ubiquitin pathway cause Angelman syndrome These genes attach the small molecule ubiquitin to other proteins and so modify their function. The end result is enhanced neuronal excitation Description of different drug classes and mechanisms of action Therapeutic drug treatment: class 1 For tonic-clonic, partial, temporal lobe seizures: Enhance the activity of GABAergic systems: Benzodiazepines (BDZs e.g. diazepam, clonazepam) are drugs that enhance the activity of GABA. They bind to a regulatory site on the GABA A receptor and increase the affinity of the receptor for GABA. Barbiturates (e.g. phenobarbital) prolong the time that GABAactivated Cl- channels stay open when the GABA A receptor is occupied. Vigabatrin inhibits GABA transaminase (decreases metabolism of GABA). Note: may provoke absence seizures. Tiagabine inhibits GABA uptake (increases the concentration of GABA in the extracellular space). Note: may provoke absence seizures. Benzodiazepines are given intravenously or via anal suppository to treat status epilepticus but are usually too sedative for prophylactic use in other epilepsies. Oral BDZs are used sometimes in patients who do not respond well to other treatments. Therapeutic drug treatment: class 2 For tonic-clonic, partial, temporal lobe seizures – may provoke absences Use-dependent block of voltage-gated sodium channels: Carbamazepine, phenytoin: These drugs reduce the likelihood of action potentials firing at high frequencies but have relatively little effect at low frequencies. control frequency of firing + drug stimulus Their binding (and hence blocking action) on the voltage-gated sodium channels is state-dependent (bind to and stabilize the inactivated state). Therapeutic drug treatment: class 3 Drugs for treating absence seizures only: Ethosuximide: Mechanism uncertain. Thought to work by blocking T-type voltage-gated Ca2+ channels in thalamic neurons. These channels are important for the generation of rhythmic activity in the neurons. Not useful for tonic-clonic seizures Therapeutic drug treatment 4: Drugs useful for both tonic-clonic and absence seizures: Lamotrigine: Use-dependent blocker of sodium channels. Sodium valproate: Mechanism uncertain. Combines a weak blocking action on voltage-gated sodium channels with a weak inhibition of GABA transaminase. Associated with fetal abnormalities. Therapeutic drug treatment: class 5 Other drugs thought to work via different mechanisms: Gabapentin, pregabalin: Molecular target is the a2d-subunit of voltage-gated Ca2+ channels so they probably work by inhibiting Ca channel function and so reducing release of excitatory neurotransmitter. Retigabine (Ezogabine in USA): Acts by enhacing opening of K+ channels of the KCNQ type. Anticonvulsant effect probably due to stabilization of the resting membrane potential of neurones. Perampanel (approved in EU and in USA for partial seizures in persons >12 yo), felbamate: Thought to act as antagonists of AMPA receptors (ionotropic glutamate receptors). Levetiracetam, binds to a synaptic vesicle protein called SV2A so it may affect neurotransmission – briveracetam licenced for use in Europe and US from Jan-Feb 2016. Topiramate, zonisamide: Mechanism(s) uncertain. END