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25. Epilepsy 4. Anti-Seizure Drugs.doc

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Mac Burnham

E PILEPSY 4 – D RUG T HERAPY FOR E PILEPSY Outline  Introduction – Why treat seizures?  Terminology  General Characteristics of Anti-Seizure Drugs  Principles of Anti-Seizure Drug Therapy  Prognosis for Seizure Control  Epilepsy Syndromes and Intractable Seizures  Drugs in Detail 1 INTRODUCTION • Most people with seizures are normal between attacks, and seizures themselves are usually brief and relatively harmless. Why treat seizures? The answer is that seizures have an impact on human life that is far out of proportion to their medical significance. o Seizures look strange, even frightening, and the public reacts badly to them. People with uncontrolled seizures may face the loss of friends, jobs, and housing. o In addition, people with uncontrolled seizures are not permitted to drive motor vehicles. Drivers' licenses are canceled with the first seizure and reinstated only if the seizures are perfectly controlled for a year. o Thus, seizure control becomes a major issue in peoples' lives, and therapy is important. • Drug therapy is always the first therapy that is tried. Query: Should drug therapy be offered first? • Firstly, don’t treat the first seizure unless the EEG shows brain abnormalities. • Dr. Burnham thinks he would opt for potential surgery before trying drugs. Or diet. Query: How about the co-morbidities? • Memory problems • Depression • Anxiety 2 TERMINOLOGY • A large number of drugs suppress seizures (e.g., most hypnotics [sleeping pills], sedatives [generally anxiolytics], and anesthetics). o All the downers stop seizures. Almost all the downers are now thought to work through the GABA sAstem and GABA is A major control against seizure activity  The problem with GABA -related drugs is that they space you out A  Recall: the sleep system is located in the basal forebrain and basically a GABAergic system which inhibits all the arousal systems. So it makes sense that taking GABAergic drugs also makes you sleepy o When the GABA sysAem is compromised, the brain just goes into immediate and violent seizures. • A small number of the safest and least toxic drugs are used in the therapy of epilepsy (not all GABAergic). • These are called “antiseizure drugs”, “antiepileptic drugs” (AEDs) or, more commonly, “anticonvulsants”. • “Anticonvulsant” is not an ideal term, since many seizures do not involve convulsions. 3 General Characteristics of Anti-Seizure Drugs • Anti-seizure drugs do not cure epilepsy; they simply suppress seizures on a temporary basis. They just elevate your seizure threshold. Patients must take them once, twice, or three times a day, sometimes for life. o Surgery is the only potential cure for epilepsy o Compliance is a problem with anti-seizure drugs, not addiction o The older drugs are basically all variants of phenobarbital – the first new drug of the 20 century. It has a very long half-life and so do the older drugs. You only had to take them once a day and this was very good for compliance.  Almost all the newer drugs have shorter half-lives • Anti-seizure drugs are fairly safe, but some of them can cause rare, life- threatening, non–dose-related adverse drug reactions (ADRs), such as liver toxicity or suppression of bone marrow. They are not dose-related because most involve an immune response. Most ADRs (95%) however, are dose-related. o Anti-convulsant hypersensitivity syndrome  Usually starts in 6 weeks after starting new medication and usually takes atleast a few days to occur. Usually seen as fever or a rash  When it occurs, it presents as a fever with a rash. Once this starts, you have a few weeks to get off the drugs or you will die  All anti-convulsants need to have a high partition coefficient (need to be fat soluble) to cross the blood-brain-barrier. The liver is responsible for biotransforming high-partition drugs to low-partition (water-soluble) so that the kidneys can excrete them (the metabolites). • Modifications by the liver take two steps: phase 1 and 2. Phase 1 takes the molecule in question and via essentially an oxidation reaction, makes the molecule very reactive. So after the molecule goes through phase 1, it’s ready to bind other things. Normally it will then go through phase 2 in the liver, where the liver provides an enzyme that will conjugate it (add on a large water-soluble functional group) o What probably happens with the anti-convolusant hypersensitivity syndrome is that the drugs the drugs go through phase 1 (become highly reactive) but the family lacks the enzymes for the phase 2 reaction. And so you’re left with a phase 1 metabolite that’s highly willing to bind to anything it associates with. It will bind to proteins, lipids, fats etc. and cause liver toxicity, which is then followed by an autoimmune attack on the liver • These rare ADRs, which probably relate to genetic abnormalities in the patient, usually occur within the first few months of therapy. All patients should be closely monitored during this period.  Query: By a neurologist / epileptologist? Potentially lethal side-effects (e.g., anti-convulsant hypersensitivity syndrome) are one reason. General Characteristics of Anti-Seizure Drugs Continued • Most anti-seizure drugs also cause dose-related ADRs, such as stomach upsets and/or, at higher doses, sedation. • Sedation is a particular problem with the older drugs, which are chemically related to the barbiturates (phenobarbital). • Due to the ADRs, the antiseizure drugs are often perceived as unpleasant to take. Compliance is a problem; abuse is not. Query: Why wouldn’t the barbs and benzos be abused? Particularly in view of the co-morbidities? • Doesn’t really seem to happen 4 Principles Of Anti-Seizure Drug Therapy (How Are The Drugs Used?) Whom to treat. Before starting therapy, it is important to rule out pseudo- seizures (not uncommon), poisoning, or active pathology. • If active pathology is present (e.g., a growing tumor, an infection), the pathology is treated, not the seizures. • Also, before initiating therapy, it is important to make sure that the seizure problem is chronic. Occasionally people have a single seizure that is never repeated. o This happens in 10% of the population. Only time you break this rule is if the first seizure leads to an EEG which shows a definitely brain abnormality Choice of drug. Before therapy is started, the type of seizure must be carefully established. Different seizure types may require different drugs. Another reason that therapy should be started by an epileptologist. • Monotherapy, not polypharmacy. Treatment is initiated with a single drug. o Most anti-seizure drugs are sedative and had super-additive sedative effects  Twice as much seizure control lead to 4-5 times more sleepiness • In most cases, therapy is started at a low dose, and gradually titrated up to normal dose levels. • If the first single drug that is tried is not effective, another single drug is tried. Eventually, if the seizures are drug resistant, polypharmacy is attempted. • Note: The recent advent of new compounds with fewer drug interactions has reawakened an interest in “rational” polypharmacy. Drug interactions. Anti-seizure drugs interact with each other and also with the drugs used for a variety of other disorders. • These interactions – which tend to be pharmacokinetic involving increases or decreases in blood levels - are too numerous to discuss. • A general rule of thumb is that: o valproate tends to (notorious for) increase blood levels of other drugs by inhibiting hepatic enzymes, while o phenobarbital, phenytoin, and carbamazepine tend to decrease blood levels of other drugs by inducing hepatic enzymes. • Several of the anti-seizure drugs, including phenytoin and carbamazepine, decrease the blood levels (and effectiveness) of oral contraceptive drugs by inducing enzymes of the cytochrome P450 system in the liver. Use of blood levels to regulate therapy. Therapeutic blood concentrations are now known for all of the older anti-seizure drugs. Monitoring of anticonvulsant blood concentrations is a standard practice with these drugs. At the start of therapy, or whenever dosage is adjusted, blood samples are taken to determine whether concentrations are in the therapeutic range. • Most of the dosing done on the anticonvulsant drugs, particularly the oldest ones, is based on blood levels. o When a drug is started or when a dose is adjusted, they will take blood samples and send them out to a lab o This is unique for anti-convulsant drugs because you can’t tell whether or not anti-seizure drugs are working. It may have raised the seizure threshold but there’s no way to know. Therefore check blood levels. o If the drug is having a bad effect on the kidney, liver, or bone marrow, you can pick this up from the blood samples. Hypersensitivity syndromes as well as compliance are also picked up from the blood Why is this necessary for the anti-seizure drugs? • The same blood samples are used to check for the occurrence of adverse drug reactions (ADRs) involving liver, kidney, or blood toxicity. Compliance. Noncompliance is an important cause of failure in anti-seizure drug therapy. It is also revealed by the blood tests, which can indicate that the patient is not taking the medication. • Compliance can be improved by programs that provide the patient with information about seizure disorders and the ways in which anti-seizure drugs control them. • Withdrawal of drugs. If a patient has no seizures or EEG abnormalities for several years, anti-seizure drugs may be slowly withdrawn. Children outgrow a number of types of childhood seizures (e.g., absence seizures), and even adults occasionally outgrow their attacks. o It is important to note that, except in hospital, anti-seizure drugs should never be withdrawn quickly. Rebound seizures may occur, and even status epilepticus if you withdraw the drugs quickly. o This is particularly true with the barbiturates (phenobarbital) and the benzodiazepines (clonazepam, clobazam). Even alcohol.  This is because they are GABA agonists! Drug therapy during pregnancy. Most women taking anti-seizure drugs remain well controlled during pregnancy. • It is believed that the risks of seizures to the fetus are greater than the risks related to anti-seizure drugs. • There is a slightly increased incidence of fetal malformations in the children of epileptic mothers, however, and this relates in part to the drugs they take. • In the general population, the incidence of fetal malformations is about 2%. In women with seizures, it is slightly higher at about 3%. • It remains at 3% in women taking only one anti-seizure drug, but rises t
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