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Treatment of Epilepsy: Maha M. Saber, MD, MRCP (UK) Assistant Professor of Pharmacology, UOS
Treatment of Epilepsy: Maha M. Saber, MD, MRCP (UK) Assistant Professor of Pharmacology, UOS
Treatment of Epilepsy: Maha M. Saber, MD, MRCP (UK) Assistant Professor of Pharmacology, UOS
OBJECTIVES
At the end of this class, you should be familiar with:
(AEDs)
General mechanisms of action of AEDs Clinical use and monitoring of AEDs Demonstration of important pharmacokinetic and pharmacotherapeutic principles of individual agents
EPILEPS Y
q
neuronal discharge.
q
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Drugs that are effective in seizure reduction accomplish this by a variety of mechanisms, including:
blockade of voltage-gated channels (Na+ or Ca2+), of inhibitory GABAergic impulses, or interference with excitatory glutamate transmission.
enhancement
Some antiepileptic drugs appear to have multiple targets within the CNS, whereas the 4/29/12 mechanism
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(4) Unknown
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Drug Choice
Choice
the
patient
specific variables (for example, age, comorbid medical conditions, lifestyle, and other preferences), and of the drug, including cost and interactions with other medications. newly diagnosed patients, monotherapy is instituted with a single agent until seizures are controlled or toxicity occurs.
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characteristics
In
Drug Choice
Compared
to those receiving combination therapy, patients receiving monotherapy exhibit better adherence and fewer side effects.
If
seizures are not controlled with the first drug, monotherapy with an alternate antiepileptic drug(s), or vagal nerve stimulation should be considered.
An awareness of the antiepileptic drugs available, including their mechanisms of action, pharmacokinetics, potential for drugdrug interactions, and adverse effects, is essential for successful therapy.
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the past 20 years, new antiepileptic drugs have been introduced, some of which have potential advantages in terms of pharmacokinetics, tolerability, and lesser risk for drug-drug interactions when compared with the older agents used to treat epilepsy. new drugs, which include gabapentin, lamotrigine, topiramate, levetiracetam, oxcarbazepine, zonisamide, are labeled second generation when compared with older antiepileptics, such as phenobarbital, phenytoin, carbamazepine, ethosuximide, divalproex and valproic acid.
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These
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Benzodiazepines
Benzodiazepines Diazepam,
bind to GABA inhibitory receptors to reduce firing rate. and lorazepam are most often used as an adjunctive therapy for myoclonic as well as for partial and generalized tonicclonic seizures. is available for rectal administration to avoid or interrupt prolonged generalized tonic-clonic seizures or clusters. has a shorter half-life but stays in the brain longer than diazepam.
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Diazepam
Lorazepam
Carbamazepine
Carbamazepine
reduces the propagation of abnormal impulses in the brain by blocking sodium channels is effective for treatment of partial seizures and secondarily generalized tonic-clonic seizures. It is also used to treat trigeminal neuralgia and in bipolar disease.
Carbamazepine
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Carbamazepine
Pharmacokinetics:
Carbamazepine may be incompletely absorbed (different brands may have different bioavailability)
It
Carbamazepine
Adverse Effects:
patients with absence The epoxide metabolite ofseizures because it the drug has been implicated in causing blood dyscrasias. A may cause an increase in seizures. characteristic rash may develop early in
Divalproex
Divalproex
sodium is a combination of sodium valproate and valproic acid and is reduced to valproate when it reaches the gastrointestinal tract. was developed to improve gastrointestinal tolerance of valproic acid. All of the available salt forms are equivalent in efficacy (valproic acid and valproate sodium). products are available in multiplesalt, dosage forms and extended-release formulations. Therefore the risk for medication errors is high, and it is essential to be familiar with all preparations. 4/29/12
It
Commercial
Divalproex
Pharmacokinetics:
Valproate inhibits metabolism of the CYP2C9, UGT and epoxide hydrolase systems. Valproate is bound to albumin (greater than 90 percent), which can cause significant interactions with other highly protein bound drugs.
Adverse Effects:
Phenytoin
Phenytoin is effective for treatment of partial seizures and generalized tonic-clonic seizures and in the treatment of status epilepticus. Mechanism of Action: Phenytoin blocks voltage-gated sodium channels by selectively binding to the channel in the inactive state and slowing its rate of recovery. At very high concentrations, phenytoin can block voltage-dependent calcium channels and interfere with the release of monoaminergic neurotransmitters. Pharmacokinetics: The drug is 90% bound to plasma albumin. Phenytoin is an inducer of drugs metabolized by the CYP2C, and CYP3A families and the UGT enzyme system. Phenytoin exhibits saturable enzyme metabolism at a low serum concentration; thus knowledge of zero- order pharmacokinetics and population parameters is important for dosing adjustment. Small increases in a daily dose can produce large increases 4/29/12 in the plasma
Phenytoin
Adverse Effects:
Adverse Effects
Ataxia, diplopia, nausea, drowsiness, slow mentation Hirsutism, gingival hyperplasia, facial coarsening Long-term use may lead to development of peripheral
Foetal hydantoin syndrome Never give faster than 50 mg/min I.V. (cardiac arrhythmias and
Fosphenytoin
qFosphenytoin
(IM). Phenytoin sodium should never be given IM because it can cause tissue damage and necrosis.
qFosphenytoin
for medication error to occur. The trade name of fosphenytoin is Cerebyx, which is easily confused with 4/29/12
Lamotrigine
Lamotrigine
is effective in a wide variety of seizure disorders, including partial seizures, generalized seizures and typical absence seizures.
Mechanism of Action:
Lamotrigine
Pharmacokinetics:
The
Lamotrigine
Adverse Effects:
Sedation, Rapid
titration to high serum concentrations of lamotrigine have been reported to cause a rash, which in some patients may progress to a serious, life-threatening reaction. has also been shown to be well tolerated by the elderly population with partial seizures due to the relatively minor adverse effects when titrated slowly.
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Lamotrigine
Gabapentin
It is approved as adjunct therapy for partial seizures and for treatment of postherpetic neuralgia Mechanism of Action:
Gabapentin
is an analog of GABA. However, it does not act at GABA receptors nor enhance GABA actions, nor is it converted to GABA. precise mechanism of action is not known.
Its
Pharmacokinetics:
Gabapentin
exhibits nonlinear pharmacokinetics due to its uptake by a 4/29/12 saturable transport system from the gut.
Phenobarbital
It
was synthesized in 1902 and brought to the market in 1912 by Bayer. The primary mechanism of action is the enhancement of inhibitory effects of GABA-mediated neurons. primary use for phenobarbital in epilepsy is in treatment of status epilepticus. to interaction with the cytochrome P450 enzymes as an inducer, and adverse effects of sedation, cognitive impairment, and potential for osteoporosis, this drug should only be considered for chronic therapy once a patient is found to be 4/29/12
The
Due
Clonazepam
Long-acting Efficacious
benzodiazepine
frequency of GABA-A
Ethosuximide
It
reduces propagation of abnormal electrical activity in the brain, most likely by inhibiting T-type calcium channels. is effective in treating only primary generalized absence seizures. Use of ethosuximide is limited because of this very narrow spectrum
It
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Topiramate
Topiramate
possesses several actions that are believed to contribute to its broad spectrum of anti-seizure activity. is effective and approved for use in partial and primary generalized epilepsies. It is also approved for treatment of migraine. blocks voltage-dependent sodium
Topiramate
Mechanism of Action:
Topiramate
channels;
it
has been shown to increase the frequency of chloride channel opening by binding to the GABAA receptor. 4/29/12
Topiramate
Adverse effects:
Somnolence, Glaucoma,
weight loss, and paresthesias; renal stones are reported. oligohidrosis, and hyperthermia have also been reported. The latter are specifically related to the carbonic anhydrase activity. It inhibits CYP2C19 and is induced by phenytoin, and carbamazepine. Lamotrigine is reported to cause an increase 4/29/12 in topiramate concentration.
Drug Interaction:
Low therapeutic index When adding a drug that may alter levels of an initial drug,
to alter
Women with epilepsy are often very concerned about pregnancy and what the medications will do to the development of the baby. is the most important component. All women should be on high doses of folic acid prior to conception. and barbiturates should be avoided.
Planning
Divalproex Switching
Treatment Algorithm
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Summary
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Summary
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