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26. Epilepsy 5. Anti-Seizure Drug Mechanisms. Molar.doc

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Mac Burnham

E PILEPSY 5: A NISEIZURE DRUG MECHANSIMS Read for Next Lecture: Francis et al. Outline : • Lessons from history • Molar Questions (whole patient) about Mechanism • Molecular Mechanisms • Molar Questions Reviewed • Novel Mechanisms Proposed for the new anti-convulsant drugs which claim to be working via novel mechanisms 1. Lessons from History Antiseizure Drugs: A Brief History reference: Krall et al. 1978  don’t memorize specific dates but remember the sequence th 19 Century • Bromides o Began to use bromides to treat epilepsy. They were sedative and anti-convulsant. o They were toxic and people were institutionalized due to bromide use 1911 • Phenobarbital (proved that anti-seizure drugs needn’t be toxic) o used as a day-time sedative, but realized it was stopping seizures as well. o Replaced the bromides and for 20 years it was the only drug for epilepsy o Problem was that it made you very sleepy (sedative effects) 1938 • Phenytoin (diphenylhydantoin) (anti-seizure drugs needn`t be highly sedating) o Much less sedating than phenobarbital and became one of the biggest selling drugs in the world (right around WW2). o Really revolutionized testing via animal testing 1950s • Many – mostly obsolete (mephobarbital, phensuximide) except for primidone, trimethadione (different drugs required for different seizure types) o Primidone is a prodrug for phenobarbital o Trimethadione is no longer used, replaced by ethosuximide. But it told us that there could be drugs for absence seizures. It makes tonic-clonic seizures worse. 1960s • Ethosuximide o Stopped making trimethadione because ethosuximide was much better (less sedation, side effects etc.)  Strict drug development legislation after thalidomide, the sedative/anti-nausea that was teratogenic. Caused many birth defects. 1970 • carbamazepine, clonazepam, valproate (drugs can be broad spectrum) o Valproate along with clonazepam were important because it showed that you could have broad-spectrum drugs (anti-absence and anti-tonic-clonic) 1978 • NIH (national institute of health) program (Krall et al. 1978) o Realized there were no new anti-convulsant drugs in the pipeline so put into place a program. Offered to test new anti-consulsant drugs for free if you sent them (preclinical testing). Because of this, you got a whole new wave of anti-convulsant drugs in the 90s. 1990 • Start of the “new” anti-seizure drugs (reference on new drugs and drugs in development: yearly Eilat conferences) So we learned that anti-convulsants: • Don’t have to be toxic • Don’t have to be very sedating • Different drugs have to used to treat different seizures, atleast the older drugs • Broad-spectrum drugs were possible 2. Molar Questions about anti-seizure drugs I) Why are the therapeutic concentrations so high? Except for the benzodiazepines, all of the anti-convulsant drugs work at uM plasma -9 -6 concentrations. (nM or 10 , uM or 10 , mM).  Nanomolar is the concentration at which the opioids, anti-psychotic, anti-anxiolytic and the majority of our CNS active drugs are going to work  In the mM concentration, you have alcohol and the general anesthetics II) Why do we need different drugs for tonic-clonic and absence? (applied to the older drugs) The puzzle of absence seizures are very different from other seizures: • Different EEG pattern o 3/s spike and wave • Different drug response o respond to ethosuximide whereas phenytoin makes them worse • May or may not involve PDEs o Paroxysmal depolarization events • Are they epilepsy? o Yes they seem to bKids with absence, if they don’t outgrow them by their teenage years, will develop tonic-clonic III) Why are complex partial seizures so drug resistant? • Clinical fact: they are o Why do they resistant drugs that stop tonic-clonic seizures. IV) Variability of anti-seizure and sedating anesthetic properties in barbiturates • Some of the barbiturates will stop seizures without making you too sleep whereas other barbs will have their anti-convulsant effects at about the same dose as their hypnotic and anesthetic effects. Example below: • Clinical facts: PHB (phenobarbital) vs. PB (pentabarb; only anesthetic) V) What’s different about “broad spectrum” drugs VI) Why do anti-absence drugs exacerbate tonic-clonic seizures and vice-versa? 3. Molecular Mechanisms of Anti-Seizure Drug Action: Traditional Drugs For many years, we had to say that we didn’t know how the anti-seizure drugs worked. The local theory was “membrane expansion”. In the past 25 years, we have discovered 3 major mechanisms of action involving: 1) VDSC: voltage dependent sodium channels 2) the GABA system 3) T-type calcium channels  Important “breakthrough” in the work of anti-convulsant drugs happened in the 1980s: Work of Macdonald and McLean – work at therapeutic concentrations, if not, it is not relevant (“total” plasma concentration versus “free”)  Plasma concentrations are the concentrations in the blood water plus the drug that’s bound the plasma proteins • Almost all clinical measurements are done on plasma. This is called the “total” plasma concentration  What the receptor sees in your body is not the plasma concentration, but the concentration in plasma water: free concentration. What goes out of the blood stream and into the peripheral tissues is the concentration of drug in the plasma water. This is the relevant concentration because this is what goes into the brain. o They were working with cultured neurons (take baby rat spinal cords, put the undifferentiated neurons in dish with food, water, oxygen and they grow. They divide and form a network of neurons – kind of like a miniature brain. o Important thing they said was you must work at therapeutic concentrations.  Prior research was being done on drug levels that were much higher than therapeutic levels. At this concentration, drugs (e.g., phenytoin) binds all sorts of protein. People were reporting all sorts of drug-protein interactions. When McDonald and Mclean used phenytoin, using electrical stimulation to make their cells in the cultured dish fire, they found that phenytoin would keep their cells from firing fast. The cells would fire at 10/s but would no longer fire at 100/s. This suggested that they were stopping AP in the axon. This proved to be what they were doing. They found that phenytoin was binding to the VDSC. Found that carbamazepine had the same mechanism of action. 1) Drugs That Bind To The VDSC Which drugs bind to the VDSC? Traditional: • Phenytoin o Made by modifying the phenobarbital molecule, but by modifying it, they unknowingly changed its target. Went from GABA reAeptor to targeting VDSC. This is true for many drugs. Small changes of a drug lead to it binding to a whole different receptor system. • Carbamazepine New (1990+): • oxcarbazepine o Recall this is the one invented at the same time as carbamazepine but wasn’t marketed till carbamazepine came off-patent. • lamotrigine (one mech) • topiramate (one mech) o Also a GABA aAonist as well as an antagonist for non-NMDA glutamatergic receptors • zonisamide (one mech) o Also T-type calcium channel inhibitor and binds to GABA receptors, facilitating serotonergic and dopaminergic activity What is the VDSC? The voltage-dependent sodium channel initiates neuronal action potentials. It exists in three states: resting, active and inactivated. • These drugs do not block the VDSC, they simply bind to the inactive configuration and keep it in the refractory (inactivated) phase for longer What do they do to the VDSC? Hold it in the “inactive” state a split second longer. Essentially they extend the refractory period. Each time the neuron fires, the sodium channel cycles through its “active,” “inactive,” and “resting” states. It is believed that these drugs hold the channel a little longer in its inactive state. This means that the neuron can fire at moderate rates (e.g., those involved in normal activity) but not at very rapid rates (those involved in seizures).  Use-dependent: the important thing is the use your brain is undergoing. E.g., phenytoin will stop 100 Hz firing, but will do nothing if you’re only in beta wave activity. Spectrum of action of VDSC-binding drugs?  Good for tonic-clonic and simple partial (not temporal lobe origin)  Less good for complex partial, simple partial (of temporal lobe origin) 2) Drugs That Enhance The Activity Of The GABA-A System Which drugs enhance GABA-A activity? Traditional: • Phenobarbital • Clonazepam • Clobazam • Diazepam (i.v. for status) • Lorazepam (i.v. for status) • (valproate??) New (1990+): • Vigabatrin • Tiagabine • Progabide (only France) o Probably the only drug we have which is an agonist for the GABAA receptor site • Felbamate (one mech) • Topiramate (one mech) • Zonisamide (one mech) What is the GABA-A System? GABA-A is the main inhibitory transmitter system of the brain. The GABA-A receptor opens a Cl- which fixes the potential of the soma near –70 mV.  If you give someone a GABA anAagonist, the person will go into seizures and die within a minute. It is a very important syst
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