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Pharm Chapter 15: Pharm of Abnormal Electrical Neurotransmission in the CNS Control of brain electrical signals, is done by ion channels - - Problems with ion channels can cause rapid, synchronized, uncontrolled spread of electrical activity, which is the basis of a seizure Epilepsy – condition that causes a tendency to get seizures o Symptoms depend on where the seizure activity is happening in the brain Include motor problems, loss of consciousness, sensation problems, or higher order problems like memory, language, etc. Lesions aren’t necessary for a seizure though o Acute changes in availability of excitatory or inhibitory neurotransmitters can cause seizures Two parts of the CNS that work to prevent repetitive and synchronous firing that happens in seizures: - - The refractory period – prevents repetitive firing in neurons by inducing sodium channel inactivation, and potassium channel-caused hyperpolarization o Throughout an action potential, the sodium channel goes through three states: Closed – before depolarization, during repolarization Open- during depolarization Inactivated – just after the peak of depolarization So what state it’s in depends on the membrane potential o Since sodium channels become inactivated in response to depolarization, action potentials are intrinsically self-limiting They won’t recover from the inactivated state until the membrane is repolarized enough Potassium channel opening repolarizes the cell, but the high potassium efflux temporarily hyperpolarizes the membrane beyond its resting membrane potential This further increases the time before a new action potential can happen o So sodium and potassium channels that act normally, will limit the frequency of firing, and therefore protect from seizures Surround inhibition - neural networks can restrict action potentials to a specific area, by activating nearby interneurons to release inhibitory GABA signals to the surrounding neurons o So the action potential goes in the neurons it’s supposed to, and no others in the area Generalized seizures – involves both cerebral hemispheres All seizures have abnormal synchronous discharges, it’s their characteristic feature - For this to happen, protective mechanisms have to fail at both the cellular and network levels - The cause of these changes that cause failure can be primary (ex: genetic problem with ion channel), secondary (ex: change in neuron environment), or a combo of both Focal seizures – localized seizures restricted to just one hemisphere - - - - Happens in three steps: o Initiation at the cellular level by an increase in electrical activity o Synchronization of surrounding neurons o Spread to adjacent regions of the brain Seizures are initiated by a sudden depolarization in a group of neurons o This sudden change, called a paroxysmal depolarizing shift (PDS), causes the making of an abnormally rapid train of action potentials o Changes in the ECF, like in a lesion, can greatly affect neuron burst activity An increase in ECF potassium would blunt effects of potassium-caused hyperpolarization, by decreasing the magnitude of the potassium gradient between the outside and inside of the cell (so potassium doesn’t want to leave) An increase in excitatory neurotransmitters, or triggering of excitatory receptors by exogenous stuff, could increase burst activity Increased burst activity can also happen from things going on in the cell, like abnormal channel conductance, or membrane changes Because of surround inhibition, local discharges are usually contained and localized, and don’t cause problems o These local discharges are seen on electroencephalogram (EEG) as sharp interictal spikes These spikes can be used to localize seizures when the patient isn’t having one at that moment o Ways surround inhibition can be overrided: Repetitive firing of neurons increases ECF potassium, which weakens potassium-mediated hyperpolarization, allowing seizure activity to spread Rapidly firing neurons also open depolarization-sensitive NMDA channels, and accumulate calcium in their synaptic terminals Both of those increase the chances of signal propagation and local synchronization GABA-mediated inhibition can be decreased by exogenous stuff, GABA neuron degeneration, or receptor changes This is usually the most important cause of surround inhibition problems It’s a major factor in allowing synchronization of a seizure focus If the synchronizing focus is strong enough, the abnormal synchronized firing from a small neural network will spread to neighboring areas of the cortex o During this spread, the patient may feel an aura, which is a conscious “warning” of the spread of the seizure - Ex: a sense of fear and confusion, memory problems (like déjà vu), language problems, change in sensations, or smell hallucinations Jacksonian march – when the symptoms spread down the motor homunculus, from hand to arm and then leg, in the order they’re represented Focal seizures can become generalized by spreading along connections that involve both cerebral hemispheres - This is called secondary generalized seizures U fibers connect areas of the cortex The corpus callosum allows spread between cerebral hemispheres The thalamus has projections to the cortex Once seizure activity spreads to involve both hemispheres, the person usually loses consciousness The most common secondary generalized seizure is the tonic-clonic type (grand-mal) o Tonic phase – GABA inhibition is lost, allowing continuous firing that causes contraction of both agonist and antagonist muscles o Clonic phase – as GABA inhibition starts to come back, it oscillates with the excitatory signals, causing clonus (shaking) o Postictal period – when GABA inhibition fully returns, the patient becomes flaccid and unconscious until normal brain function returns o Page 229 bottom pic – brain voltage and electrolytes through the tonic-clonic phases Primary generalized seizures start from the central brain regions, & then spreads to both hemispheres - - Unlike focal seizures, which start at a collection of neurons, and then spreads Might not be any aura in primary generalized seizures The best understood primary generalized seizure is the absence seizure (aka petit mal seizure) o Absence seizures are characterized by sudden interruptions in consciousness, that are often accompanied by a blank stare and occasional motor symptoms, like rapid blinking and lip smacking o Absence seizures are thought to be caused by abnormal synchronization of thalamus and cortex cells (thalamocortical tracts) o People with absence seizures have EEG readings similar to slow wave (stage 3) sleep Relay neurons connecting the thalamus to the cortex have two different states, depending on the level of wakefulness o In the awake state, these neurons work in transmission mode, where incoming sensory signals are sent to the cortex o During sleep, the temporary bursting activity of a dendrite T-type calcium channel changes the incoming signals, so that output to the cortex has an oscillatory firing rate Looks like “spike and wave (dome)” on EER In this slow wave sleep state, sensory info is not sent to the cortex o Absence seizures can activate T-type calcium channels during the awake state o o The T-type calcium channel is only active when the cell is hyperpolarized T-type calcium channels can be activated during the awake state by: Increase in intracellular potassium Increase in GABA input from the reticular nucleus Loss of excitatory input Classifications of seizures: - - Focal seizures – involves one hemisphere at a focal (localized) point o Focal without altered mental status – aka simple partial, and consciousness isn’t lost Symptoms depend on where in the cortex the seizure is Ex: repetitive motor movements (motor cortex), paresthesia (sensory cortex), flashing lights (visual cortex) The patient stays conscious in focal seizures without altered mental status The seizure will spread to ipsilateral regions of the cortex Ex: Jacksonian march o Focal with altered mental status – so aka partial complex, consciousness is ↓ Symptoms come from abnormal activity of the temporal lobe or frontal lobe Consciousness will be altered in focal seizures with altered mental status Ex: stopping of activity, loss of contact with reality Often will see involuntary “automatisms,” anywhere from simple repetitive movements like lip smacking, to highly skilled activities Usually preceded by an aura They won’t remember anything from the ictal phase o Focal seizure with secondary generalization – focal spread to both hemispheres Starts with symptoms of focal seizures, and then evolves into a tonic-clonic seizure with sustained (tonic) contraction, followed by rhythmic movements (clonus) In focal seizures with secondary generalization, the person will lose consciousness Preceded by an aura Primary generalized seizures – from central brain areas to both hemispheres o Absence (petit mal) seizure Shows sudden, brief interruption of consciousness, blank stare, sometimes motor symptoms like lip smacking No aura o Myoclonic seizure- brief (1 second or less) muscle contraction Symptoms can happen in individual muscle, or generalize to all muscle groups of the body Happens in systemic diseases o Tonic-clonic (grand mal) seizure – shows sustained contraction (tonic) followed by rhythmic movements (clonus) Consciousness is lost Preceded by an aura Antiepileptic drugs (AED’s) work by affecting ion channel activity - - Four types: o Drugs that block sodium channels to inhibit o Drugs that inhibit calcium channels o Drugs that enhance GABA-mediated inhibition o Drugs that inhibit glutamate receptors They all act pleiotropically though, which means they have many different effects o Ex: valproic acid stabilized sodium channels, but also affects T-type calcium channels and GABA o This makes it so that many of the antiepileptic drugs are interchangeable, and the main deciding factor on what drug to pick is the side-effects o So classifications are made based on the main target of the drug Drugs that enhance sodium channel-mediated inhibition (aka sodium channel blockers): - - - Depolarization of the neuron membrane causes sodium channel inactivation o This prevents repetitive firing Antiepileptic drugs that act on sodium channels are very specific for treating focal and secondary generalized seizures o Don’t have much of an effect on absence seizures o This is due to the use (state)-dependent effect of sodium channel blockers Antiepileptic drugs that work directly on sodium channels to increase channel inactivation, and therefore increase inhibition at the single cell level: o Phenytoin, carbamazepine, lamotrigine, lacosamide, and valproic acid Phenytoin: o Phenytoin acts directly on the sodium channel to slow the transition from inactivated to closed states (so keep inactivated longer) So phenytoin increases the threshold for action potentials, and prevents repetitive firing (aka prolongs the refractory period) o This stabilizes the seizure focus by preventing the paroxysmal depolarizing shift (PDS) that initiates the focal seizure o Phenytoin also prevents spread of seizure activity to other neurons This is why it works great for secondary generalized seizures o Phenytoin targets sodium channels in a use (state)-dependent manner So only channels opened or closed a lot, like those involved in the PDS, are likely to be inhibited This use-dependency decreases the effects of phenytoin on spontaneous normal neuron activity, and avoids the adverse effects seen in drugs that promote GABA o - - - Phenytoin is the major drug of choice for focal seizures and tonic-clonic seizures Phenytoin is not used for absence seizures o Most of the phenytoin binds to plasma albumin o Phenytoin is inactivated by the liver o A typical dose of phenytoin has a plasma half-life of 24 hours o Small increases in dose of phenytoin can cause large and often unpredictable increases in plasma drug concentration This increases the risk of adverse effects of phenytoin, which include ataxia, nystagmus, coordination problems, confusion, gingiva hyperplasia, megaloblastic anemia, hirsutism, facial coarsening, and systemic skin rash o Drugs that inhibit hepatic P450 enzymes will increase the amount of plasma phenytoin o Drugs that induce P450 enzymes, like antiepileptic carbamazepine, increase phenytoin metabolism (clearance) Carbamazepine o Carbamazepine is a sodium channel blocker that slows the transition of the channel from inactivated to the closed state (prolongs inactivation) o This suppresses a seizure focus by preventing the PDS, and prevents spread of activity from the seizure focus o Carbamazepine is often the drug of choice for focal seizures o The half-life of carbamazepine is 10-20 hours Chronic use will decrease the half-life, from P450 enzyme induction causing them to adapt So you have to take several doses of carbamazepine daily o Since metabolism of carbamazepine is linear (shows first order kinetics), carbamazepine is the more preferred choice than phenytoin for people with possible drug interactions Lamotrigine - another sodium channel blocker that slows sodium channel recovery from the inactivated state o Lamotrigine is a good alternative to phenytoin and carbamazepine for focal and tonicclonic seizures o Lamotrigine can also work for absence seizures, and is used when ethosuximdie and valproic acid aren’t Lacosamide - enhances slow inactivation of sodium channels, without blocking the channel directly o Lacosamide is an alternative to phenytoin and carbamazepine for focal seizures, and has fewer drug-drug interactions Drugs that inhibit calcium channels: - - There’s two types of calcium channel blockers: o Those that inhibit the T-type calcium channel o Those that inhibit the high-voltage activated (HVA) calcium channel The T-type calcium channel is depolarized and inactive during the awake state o - - - - - In absence (petit mal) seizures, paroxysmal hyperpolarization is thought to activate the channel during the awake state o So drugs inhibiting T-type Ca2+ channels are specifically used to treat absence seizures HVA calcium channels are important in controlling entry of calcium into the presynaptic terminal, and so they help to regulate excitatory neurotransmitter release o Drugs that inhibit HVA calcium channels tend to be pleiotropic, but are used mainly for focal seizures Ethosuximide – a specific T-type calcium channel blocker o Ethosuximide is often the first-line therapy for absence seizures It won’t work for focal or secondary generalized seizures Valproic acid – sodium and calcium channel blocker, and promotes GABA o Valproic acid has pleiotropic effects o Valproic acid slows the rate of sodium channel recovery from the inactivated state o Higher concentrations of valproic acid can limit activity of the T-type calcium channel o Valproic acid also may increase glutamate decarboxylase activity, which is the enzyme that makes GABA, and also inhibit enzymes that degrade GABA So valproic acid increases availability of GABA, and therefore GABA-mediated inhibition o Valproic acid is one of the most effective antiepileptic drugs for generalized epilepsy with mixed seizure types, probably due to all the different ways it can work o Valproic acid is also used for absence seizures that ethosuximide didn’t work for o Valproic acid can also be an alternative to phenytoin or carbamazepine for focal seizures o So valproic acid is used for all seizures Gabapentin- GABA analogue that increases GABA in neurons and glial cells, but its main antiepileptic effect is it inhibits HVA calcium channels, which decreases release of neurotransmitters like glutamate and norepinephrine o Since it’s an amino acid analogue of an endogenous a.a., it has very few drug interactions o Gabapentin is not used often though, cause it’s not as effective as the other antiepileptics Pregabalin- another GABA analogue that works mostly by inhibiting HVA calcium channels, decreasing release of neurotransmitters like glutamate and norepinephrine o Pregabalin is more potent than gabapentin o Pregabalin is used for focal seizures, especially in patients with liver problems, since it’s metabolized in the kidney, and has few drug-drug interactions Drugs that enhance GABA-mediated inhibition: - Unlike sodium and calcium channel blockers, GABA enhancers have more varied effects, and aren’t as interchangeable o This is because of the diversity of the GABAA receptors in the brain o There are 10 subtypes of GABAA receptors o - - - Benzodiazepines and phenobarbital barbiturate both increase chloride influx through GABAA channels, but benzodiazepines act on a specific type of GABAA channel, while phenobarbital acts on all GABAA channels Benzodiazepines – increase the affinity of GABA for the GABAA receptor, and enhance GABAA channel gating in the presence of GABA, which increases chloride influx through the channel o This both suppresses the seizure focus by raising the threshold of the action potential, and strengthens surround inhibition o Benzodiazepines are diazepam, lorazepam, midazolam, and clonazepam o Benzodiazepines are good for treating focal and tonic-clonic seizures o Benzodiazepines have lots of adverse effects though, like dizziness, ataxia, and drowsiness So benzodiazepines are only used for acute seizures o Clonazepam is different from other benzodiazepines, because it can inhibit T-type calcium channel currents Clonazepam acts specifically at GABAA receptors in the reticular nucleus, helping inhibition in these neurons and essentially turning off the nucleus This prevents GABA-mediated hyperpolarization of the thalamus, and indirectly inactivates the T-type calcium channel, which is the channel that causes absence seizures Still has lots of adverse effects though, so it’s nowhere near the first choice Barbiturates o Phenobarbital is a barbiturate that binds to the GABAA receptor, and increases the effect of GABA by increasing the duration of chloride channel opening o So more chloride comes in for each activation of the channel o Phenobarbital is also a weak agonist for the GABAA channel, which could increase chloride influx even more o So phenobarbital is used to treat focal seizures and tonic-clonic seizures o Unlike benzodiazepines, which can used for absence seizures, phenobarbital can actually make absence seizures worse This could be because phenobarbital works on all GABAA receptors in the reticular nucleus and thalamus relay cells, which enhances the T-type calcium currents that cause absence seizures Could also be because phenobarbital can act on GABAA channels without a ligand, unlike benzodiazepines o Phenobarbital is used mainly as an alternative treatment for focal seizures and tonicclonic seizures o It’s not used as much anymore because of its sedative effect Vigabatrin – GABA analogue that irreversibly inhibits GABA transaminase, therefore increasing GABA levels in the brain o Vigabatrin can cause serious adverse effects, like peripheral visual field defects o This limits is use, and they need to undergo visual field testing o Vigabatrin is used for kids and refractory focal epilepsy Drugs that inhibit glutamate receptors: - Glutamate is the main excitatory neurontransmitter of the CNS Excessive activation of excitatory glutamate synapses is often seen in seizures Inhibiting NMDA and AMPA glutamate receptors can inhibit the generation of seizure activity No glutamate receptor inhibitors are used clinically though, because of unacceptable behavioral adverse effects Glutamate receptor inhibitors are felbamate and rufinamide o Felbamate – doesn’t have behavioral adverse effects other NDMA blockers have This is because it is selective for a certain subunit on NMDA receptors, that isn’t expressed all throughout the brain Felbamate is a potent antiepileptic, and doesn’t have the sedative effects many of the other antiepileptics have Use of felbamate is restricted though, cause it can cause fatal aplastic anemia and liver failure Only really used for refractory epilepsy o Rufinamide – used for focal seizures and Lennox-Gaustaut syndrome (syndrome of childhood seizures) Rufinamide prolongs sodium channel inactivation May also inhibit glutamate receptors Rufinamide has show no evidence of serious adverse effects, and may be a good alternative for refractory epilepsy Simple partial seizure – they’re aware of it, there’s uncontrollable neuro problems Complex partial seizure – aura, then they go unresponsive (unaware), with automatisms, then post-ictal signs Generalized clonic tonic (grand mal) – aura, loss of consciousness, body goes rigid (tonic), then clonic (rhythmic contractions), then they lay unconscious and unresponsive, then they recover with post ictal issues Absence (petit mal seizure) – they go unresponsive with blank stare, then come out of it