SEZURE and Eplepsy by Minwoldu

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Information about SEZURE and Eplepsy by Minwoldu
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Published on February 27, 2014

Author: minwoldu

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Epilepsy: By Minyahil A Woldu Bpharm., MSc in Clincal Pharmacy Epilepsy FAMOUS PEOPLE WHO WERE AFFLICTED: FAMOUS PEOPLE WHO WERE AFFLICTED ALEXANDER THE GREAT JULIUS CAESAR NAPOLEON DOSTOEVSKY VAN GOGH DEFINITIONS: DEFINITIONS Epilepsy implies a periodic recurrence of seizures with or without convulsions . A seizure results from an excessive discharge of cortical neurons and is characterized by changes in electrical activity as measured by the electroencephalogram ( EEG ). A convulsion implies violent, involuntary contraction(s) of the voluntary muscles. Definition, Seizure.: Definition, Seizure. Latin sacire , “to take possession of”. A paroxysmal event. Abnormal , excessive , hypersynchronous electrical discharges. ~5-10% of the population will have at least one seizure. Normally there are highly differentiated electrical signals with in the brain that sustain the normal life “ Electrical rebellion ” that results in to monotonous discharge firing in synchrony across the brain Most prevalent of the neurological disorders Recurrent seizures due to a chronic, underlying process. Epilepsy ~ > 2 unprovoked seizures: Magnitude of the problem : Magnitude of the problem World wide incidence 0.3-.0.5% prevalence 5-10/1000 Ethiopia prevalence 5.2/1000 GTC 81% Partial complex 13.9 simple partial 5.7 PATHOPHYSIOLOGY: PATHOPHYSIOLOGY Seizures result from excessive excitation, or from disordered inhibition of a population of neurons. Initially, a small number of neurons fire abnormally. Then normal membrane conductances and inhibitory synaptic currents break down, excitability spreads locally ( focal seizure ) or more widely ( generalized seizure ). PATHOPHYSIOLOGY…: PATHOPHYSIOLOGY… Mechanisms that may contribute to synchronous hyperexcitability include: Alterations of ion channels in neuronal membranes Biochemical modifications of receptors Modulation of second messaging systems and gene expression Changes in extracellular ion concentrations Alterations in neurotransmitter uptake and metabolism in glial cells Modification in the ratio and function of inhibitory circuits Local neurotransmitter imbalances (e.g., glutamate , γ- aminobutyric acid [ GABA ]), acetylcholine , norepinephrine , and serotonin ) PATHOPHYSIOLOGY…: PATHOPHYSIOLOGY… Large numbers of generalized tonic-clonic ( GTC ) seizures (more than100) and multiple episodes of status epilepticus may be associated with neuronal damage . In particular, continued exposure to glutamate may contribute to neuronal damage . CAUSES ACCORDING TO AGE.: CAUSES ACCORDING TO AGE. Age determines the incidence & likely etiology of seizures & epilepsy. Neonatal period & early infancy Congenital, trauma, infection, metabolic. Drug withdrawal ( addict mothers). Inborn errors of metabolism. Idiopathic or inherited. Late infancy & early childhood Febrile Seizure:- prevalence 3-5%. febrile illness; No CNS infecn. + family Hx(febrile sz/epilepsy) 3mo-5yr(peak incid.:18mo-2yr) generalized, tonic-clonic seizures. simple or complex. Genetic, trauma, dev’tal, infecn, idiopathic. CAUSES ACCORDING TO AGE…: CAUSES ACCORDING TO AGE… Adolescence & EARLY ADULTHOOD Head trauma Infection Illicit drug use Alcohol withdrawal Brain tumor Idiopathic Older adults CVA Trauma( including subdural hematoma) CNS tumors Degenerative diseases Alcohol withdrawal Idiopathic CAUSES ACCORDING TO AGE…: CAUSES ACCORDING TO AGE… Broad age range Electrolyte imbalance Hypo-/hyperglycemia Hepatic/renal failure Endocrine disorders Hematologic disorders Vasculitides Drugs and Other Substances that Can Cause Seizures: Drugs and Other Substances that Can Cause Seizures Alkylating agents (e.g., busulfan, chlorambucil) Antimalarials (chloroquine, mefloquine) Antimicrobials/antivirals lactam and related compounds Quinolones Acyclovir Isoniazid Ganciclovir Anesthetics and analgesics Meperidine Tramadol Local anesthetics Dietary supplements Ephedra (ma huang) Gingko Drugs and Other Substances that Can Cause Seizures…: Drugs and Other Substances that Can Cause Seizures… Immunomodulatory drugs Cyclosporine OKT3 (monoclonal antibodies to T cells) Tacrolimus Interferons Psychotropics Antidepressants Basic Mechanisms: Basic Mechanisms Mechanisms of Seizure Initiation and Propagation Focal seizure activity can begin in a very discrete region of cortex and then spread to neighboring regions, i.e., there is a seizure initiation phase and a seizure propagation phase. The initiation phase is characterized by two concurrent events in an aggregate of neurons: (1) high-frequency bursts of action potentials and (2) hypersynchronization. Basic Mechanisms…: Basic Mechanisms… The bursting activity is caused by a relatively long-lasting depolarization of the neuronal membrane due to influx of extracellular calcium (Ca 2+ ), which leads to the opening of voltage-dependent sodium (Na + ) channels, influx of Na + , and generation of repetitive action potentials . This is followed by a hyperpolarizing after potential mediated by -aminobutyric acid ( GABA ) receptors or potassium ( K + ) channels, depending on the cell type. The synchronized bursts from a sufficient number of neurons result in a so-called spike discharge on the EEG. Normally , the spread of bursting activity is prevented by intact hyperpolarization and a region of " surround " inhibition created by inhibitory neurons . Basic Mechanisms…: Basic Mechanisms… With sufficient activation there is a recruitment of surrounding neurons via a number of synaptic and nonsynaptic mechanisms, including: (1) an increase in extracellular K + , which blunts hyperpolarization and depolarizes neighboring neurons ; (2) accumulation of Ca 2+ in presynaptic terminals, leading to enhanced neurotransmitter release ; and (3) depolarization-induced activation of the N-methyl-D-aspartate ( NMDA ) subtype of the excitatory amino acid receptor, which causes additional Ca 2+ influx and neuronal activation ; & (4) ephaptic interactions related to changes in tissue osmolarity and cell swelling. The recruitment of a sufficient number of neurons leads to the propagation of seizure activity into contiguous areas via local cortical connections , and to more distant areas via long commissural pathways such as the corpus callosum. Basic Mechanisms…: Basic Mechanisms… Many factors control neuronal excitability, and thus there are many potential mechanisms for altering a neuron's propensity to have bursting activity. Mechanisms intrinsic to the neuron include changes in the conductance of ion channels, response characteristics of membrane receptors , cytoplasmic buffering , second-messenger systems , and protein expression as determined by gene transcription, translation, and posttranslational modification. Basic Mechanisms…: Basic Mechanisms… Mechanisms extrinsic to the neuron include changes in the amount or type of neurotransmitters present at the synapse, modulation of receptors by extracellular ions and other molecules, and temporal and spatial properties of synaptic and nonsynaptic input. Nonneural cells such as astrocytes and oligodendrocytes, have an important role in many of these mechanisms as well. Basic Mechanisms…: Basic Mechanisms… Certain recognized causes of seizures are explained by these mechanisms. For example, accidental ingestion of domoic acid , which is an analogue of glutamate (the principal excitatory neurotransmitter in the brain), causes profound seizures via direct activation of excitatory amino acid receptors throughout the CNS. Penicillin , which can lower the seizure threshold in humans and is a potent convulsant in experimental models, reduces inhibition by antagonizing the effects of GABA at its receptor . The basic mechanisms of other precipitating factors of seizures such as sleep deprivation, fever, alcohol withdrawal, hypoxia, and infection, are not as well understood but presumably involve analogous perturbations in neuronal excitability. Similarly, the endogenous factors that determine an individual's seizure threshold may relate to these properties as well. Basic Mechanisms…: Basic Mechanisms… Knowledge of the mechanisms responsible for initiation and propagation of most generalized seizures (including tonic-clonic, myoclonic, and atonic types) remains rudimentary and reflects the limited understanding of the connectivity of the brain at a systems level. Much more is understood about the origin of generalized spike-and-wave discharges in absence seizures . These appear to be related to oscillatory rhythms normally generated during sleep by circuits connecting the thalamus and cortex . This oscillatory behavior involves an interaction between GABA B receptors , T-type Ca 2+ channels, and K + channels located within the thalamus. Thalamo cortical circuit: Thalamo cortical circuit Mechanisms of Epileptogenesis: Mechanisms of Epileptogenesis Epileptogenesis refers to the transformation of a normal neuronal network into one that is chronically hyperexcitable. There is often a delay of months to years between an initial CNS injury such as trauma, stroke, or infection and the first seizure. The injury appears to initiate a process that gradually lowers the seizure threshold in the affected region until a spontaneous seizure occurs. In many genetic and idiopathic forms of epilepsy, epileptogenesis is presumably determined by developmentally regulated events. CLINICAL PRESENTATION: CLINICAL PRESENTATION GENERAL In most cases, the healthcare provider will not be in a position to witness a seizure. Many patients (particularly those with complex partial [CP] or GTC seizures) are amnestic to the actual seizure event . Obtaining an accurate history and description of the ictal event (including time course) from a third party is important. SYMPTOMS: SYMPTOMS Symptoms of a specific seizure depend on seizure type. Although seizures can vary between patients, they tend to be stereotyped within an individual. CP seizures may include somatosensory or focal motor features. They are associated with altered consciousness . Absence seizures have only very brief (seconds) periods of altered consciousness . GTC seizures are major convulsive episodes and are always associated with a loss of consciousness . SIGNS: SIGNS Interictally (between seizure episodes), there are typically no objective, pathognomonic signs of epilepsy. LABORATORY TESTS There are currently no diagnostic laboratory tests for epilepsy. In some cases, particularly following GTC (or perhaps CP) seizures, serum prolactin levels may be transiently elevated . Laboratory tests may be done to rule out treatable causes of seizures (e.g., hypoglycemia, altered serum electrolyte concentrations, infections, etc.) that do not represent epilepsy. OTHER DIAGNOSTIC TESTS: OTHER DIAGNOSTIC TESTS EEG is very useful in the diagnosis of various seizure disorders, but the EEG may be normal in some patients who still have the clinical diagnosis of epilepsy. A serum prolactin level obtained within 10 to 20 minutes of a tonic-clonic seizure can help differentiate seizure activity from pseudoseizure activity , but not from syncope . Although magnetic resonance imaging is very useful (especially imaging of the temporal lobes), computed tomography typically is not helpful except in the initial evaluation for a brain tumor or cerebral bleeding . OTHER DIAGNOSTIC TESTS…: Partial (focal) seizures begin in one hemisphere of the brain and, unless they become secondarily generalized, result in an asymmetric seizure . Partial seizures manifest as alterations in motor functions , sensory or somatosensory symptoms, or automatisms . If there is no loss of consciousness , the seizures are called simple partial . If there is loss of consciousness , they are termed complex partial , and the patients may have automatisms , memory loss , or aberrations of behavior . OTHER DIAGNOSTIC TESTS… OTHER DIAGNOSTIC TESTS…: Absence seizures generally occur in young children or adolescents and exhibit a sudden onset, interruption of ongoing activities, a blank stare, and possibly a brief upward rotation of the eyes. Absence seizures have a characteristic two to four cycle/second spike and slow-wave EEG pattern. In generalized seizures, motor symptoms are bilateral, and there is altered consciousness. GTC seizures may be preceded by premonitory symptoms (i.e., an aura). A tonic-clonic seizure that is preceded by an aura is likely a partial seizure that is secondarily generalized. OTHER DIAGNOSTIC TESTS… OTHER DIAGNOSTIC TESTS…: Tonic-clonic seizures begin with a short tonic contraction of muscles followed by a period of rigidity. The patient may lose sphincter control , bite the tongue , or become cyanotic . The episode may be followed by unconsciousness , and frequently the patient goes into a deep sleep . Myoclonic jerks are brief shock-like muscular contractions of the face, trunk, and extremities. They may be isolated events or rapidly repetitive. In atonic seizures, there is a sudden loss of muscle tone that may be described as a head drop , dropping of a limb , or slumping to the ground . OTHER DIAGNOSTIC TESTS… International Classification of Epileptic Seizures: International Classification of Epileptic Seizures PowerPoint Presentation: Primary Types of s (focal) 31 DIAGNOSIS: DIAGNOSIS The patient and family should be asked to characterize the seizure for frequency, duration, precipitating factors, time of occurrence, presence of an aura, ictal activity, and postictal state. Physical, neurologic, and laboratory examination (SMA-20, complete blood cell count, urinalysis, and special blood chemistries) may identify an etiology. A lumbar puncture may be indicated if there is fever. DDX of seizures: DDX of seizures Syncope : Vasovagal syncope  Cardiac arrhythmia  Valvular heart disease  Cardiac failure  Orthostatic hypotension Psychological disorders:   Psychogenic seizure  Hyperventilation  Panic attack Metabolic disturbances:   Alcoholic blackouts  Delirium tremens  Hypoglycemia  Hypoxia  Psychoactive drugs (e.g., hallucinogens) Migraine:   Confusional migraine  Basilar migraineTransient ischemic attack (TIA)  Basilar artery TIA Sleep disorders:   Narcolepsy/cataplexy  Benign sleep myoclonus Movement disorders:   Nonepileptic myoclonus  Paroxysmal choreoathetosis Special considerations: in children  Breath-holding spells  Migraine with recurrent abdominal pain and cyclic vomiting  Benign paroxysmal vertigo  Apnea  Night terrors  Sleepwalking DESIRED OUTCOME: DESIRED OUTCOME The goal of treatment is to control or reduce the frequency of seizures, minimize side effects, and ensure compliance, allowing the patient to live as normal a life as possible. Complete suppression of seizures must be balanced against tolerability of side effects, and the patient should be involved in defining the balance . GENERAL APPROACH: GENERAL APPROACH The treatment of choice depends on the type of epilepsy and on drug-specific adverse effects and patient preferences. Begin with monotherapy; about 50% to 70% of patients can be maintained on one antiepileptic drug (AED), but all are not seizure free. Up to 60% of patients with epilepsy are noncompliant, and this is the most common reason for treatment failure . GENERAL APPROACH…: GENERAL APPROACH… Drug therapy may not be indicated in patients who have had only one seizure or those whose seizures have minimal impact on their lives. Patients who have had two or more seizures should generally be started on AEDs . Factors favoring successful withdrawal of AEDs include a seizure-free period of 2 to 4 years, complete seizure control within 1 year of onset, an onset of seizures after age 2 years and before age 35 years, and a normal EEG. GENERAL APPROACH…: GENERAL APPROACH… Poor prognostic factors include a history of a high frequency of seizures, repeated episodes of status epilepticus, a combination of seizure types, and development of abnormal mental functioning . A 2-year, seizure-free period is suggested for absence and rolandic epilepsy , while a 4-year, seizure-free period is suggested for simple partial , CP , and absence associated with tonic-clonic seizures . GENERAL APPROACH…: GENERAL APPROACH… According to the American Academy of Neurology guidelines, discontinuation of AEDs may be considered if the patient is seizure free for 2 to 5 years , if there is a single type of partial seizure or primary GTC seizures, if the neurologic examination and IQ are normal , and if the EEG normalized with treatment. AED withdrawal should always be done gradually. GENERAL APPROACH…: Up to 80% of patients can ……….. expect partial or complete control of seizures with appropriate treatment Antiepileptic drugs suppress seizure activity………but.…. do not cure seizures Antiepileptics are indicated when ………. there is two or more seizures occurred in short interval (6m -1y) An initial therapeutic aim is ………… to use only one drug ( monotherapy ) GENERAL APPROACH… 39 PowerPoint Presentation: When a total daily dose is increased……….. sufficient time (about 5 t 1l2) should be allowed for the serum drug level to reach a new steady-state level . The drugs are usually administered………… orally The monitoring of plasma drug levels is …. very useful Precipitating or aggravating factors ……. can affect seizure control by drugs Relapse rate when antiepileptics are withdrawn is 20 -40 % GENERAL APPROACH… 40 Factors triggering seizures: Factors triggering seizures Strobe light Stress Sleep Overeating Alcohol Drugs 41 Mechanisms of Action of Antiepileptic Drugs: Mechanisms of Action of Antiepileptic Drugs Antiepileptic drugs appear to act primarily by blocking the initiation or spread of seizures . This occurs through a variety of mechanisms that modify the activity of ion channels or neurotransmitters , and in most cases the drugs have pleiotropic effects. Mechanisms of Action of Antiepileptic Drugs…: Mechanisms of Action of Antiepileptic Drugs… The mechanisms include inhibition of Na + -dependent action potentials in a frequency-dependent manner (e.g., phenytoin, carbamazepine, lamotrigine, topiramate, zonisamide, lacosamide, rufinamide), inhibition of voltage-gated Ca 2+ channels (phenytoin, gabapentin, pregabalin), attenuation of glutamate activity (lamotrigine, topiramate, felbamate), potentiation of GABA receptor function (benzodiazepines and barbiturates), increase in the availability of GABA (valproic acid, gabapentin, tiagabine), and modulation of release of synaptic vesicles (levetiracetam). SPECIAL CONSIDERATIONS IN THE FEMALE PATIENT: SPECIAL CONSIDERATIONS IN THE FEMALE PATIENT Estrogen has a seizure-activating effect , whereas progesterone has a seizure-protective effect . Enzyme-inducing AEDs, including topiramate and oxcarbazepine , may cause treatment failures in females taking oral contraceptives. For catamenial epilepsy (seizures just before or during menses) or seizures that occur at the time of ovulation, conventional AEDs should be tried first, but hormonal therapy (progestational agents) may also be effective. Intermittent acetazolamide has also been used. SPECIAL CONSIDERATIONS IN THE FEMALE PATIENT…: SPECIAL CONSIDERATIONS IN THE FEMALE PATIENT… About 25% to 30% of women have increased seizure frequency during pregnancy, and a similar percentage have decreased frequency. AED monotherapy is preferred in pregnancy . Clearance of phenytoin, carbamazepine, phenobarbital, ethosuximide, lamotrigine, and clorazepate increases during pregnancy, and protein binding may be altered . There is a higher incidence of adverse pregnancy outcomes in women with epilepsy, and the risk of congenital malformations is 4% to 6% ( twice as high as in nonepileptic women ). SPECIAL CONSIDERATIONS IN THE FEMALE PATIENT…: SPECIAL CONSIDERATIONS IN THE FEMALE PATIENT… Barbiturates and phenytoin are associated with congenital heart malformations and facial clefts . Valproic acid and carbamazepine are associated with spina bifida (0.5% to 1%) and hypospadias . Other adverse outcomes are growth , psychomotor , and mental retardation . Some of these events can be prevented by adequate folate intake ; prenatal vitamins with folic acid (approximately 0.4 to 5 mg/day) should be given to women of child-bearing potential who are taking AEDs. SPECIAL CONSIDERATIONS IN THE FEMALE PATIENT…: SPECIAL CONSIDERATIONS IN THE FEMALE PATIENT… Higher folate doses should be used in women with a history of a previous pregnancy with a neural tube defect. Vitamin K, 10 mg/day orally, given to the mother during the last month before delivery can prevent neonatal hemorrhagic disorder. Algorithm for treatment of epilepsy. (AED, antiepileptic drug; QOL, quality of life.): Algorithm for treatment of epilepsy. (AED, antiepileptic drug; QOL, quality of life.) Non - pharmacologic: Non - pharmacologic Diet – ketogenic diets. Surgery - in selected patients with refractory focal epilepsy. vagus nerve stimulation (VNS)- affects conc. of NTs (excitatory vs inhibitory) and increases blood flow to the affected brain parts. 49 Pharmacologic approach: Pharmacologic approach Optimal management requires -AED treatment be individualized. Children. Women of Child-bearing Potential The Elderly. Specific pt conditions Optimization requires: understanding of drug mechanism(s) of action spectrum of clinical activity Pk profiles ADR 50 AED: Principles of therapy: AED: Principles of therapy Establish accurate diagnosis Select appropriate drug - established efficacy in the seizure type Generalized tonic-clonic ~60-90% controlled Absence ~70-80% controlled Partial complex ~50% controlled Do not delay treatment: fewer seizures – better prognosis Avoid sudden interruption of drug therapy……..it is.. frequent cause of status epilepticus Insufficient control - monitor plasma levels - use combination of drugs 51 AED: therapeutic use in epilepsy: AED: therapeutic use in epilepsy Partial seizures simple carbamazepine phenobarbital phenytoin (topiramate) valproate (vigabatrin) complex carbamazepine phenobarbital phenytoin (topiramate) valproate (vigabatrin) Generalized seizures tonic-clonic (grand mal) carbamazepine phenobarbital phenytoin valproate absence (petit mal) ethosuximide valproate clonazepam myoclonic valproate lamotrigine clonazepam febrile seizures in children phenobarbital Status epilepticus : diazepam, lorazepam, phenytoin 52 CNS AEs with New AEDs: 54 CNS AEs with New AEDs Ataxia Blurred Vision Cognitive Effects Dizziness Drowsiness Fatigue Headache NEW AEDS Felbamate + + + + Gabapentin + + + + + Lamotrigine + + + + + Levetiracetam + + + Oxcarbazepine + + + + + + Tiagabine + + + + Topiramate + + + Vigabatrin + + + + + Zonisamide + + + + + Chapman DP, et al. South Med J. 1997;90:L171-L180. SPECIFIC ANTIEPILEPTIC DRUGS: SPECIFIC ANTIEPILEPTIC DRUGS Carbamazepine may act primarily by inhibition of voltage-gated sodium channels . Food may enhance bioavailability . Controlled- and sustained-release preparations dosed every 12 hours are bioequivalent to immediate-release preparations dosed every 6 hours. These dosage forms, compared with immediate-release preparations, have lower peaks and higher troughs . The liver metabolizes 98% to 99% of a dose of carbamazepine (mostly by CYP3A4 ), and the major metabolite is carbamazepine-10,11-epoxide , which is active. Carbamazepine…: Carbamazepine… can induce its own metabolism ( autoinduction ); this effect begins within 3 to 5 days of dosing initiation and takes 21 to 28 days to become complete. is considered an AED of first choice for newly diagnosed partial seizures and for primary GTC seizures that are not considered an emergency. Neurosensory side effects (e.g., diplopia, blurred vision, nystagmus, ataxia, dizziness, and headache) are the most common, occurring in 35% to 50% of patients initially. It may induce hyponatremia , and the incidence may increase with age. Carbamazepine…: Carbamazepine… Hyponatremia occurs less frequently than with oxcarbazepine. Leukopenia is the most common hematologic side effect (up to 10%) but is usually transient. It may be persistent in 2% of patients. Carbamazepine may be continued unless the white blood cell count drops to less than 2,500/mm3 and the absolute neutrophil count drops to less than 1,000/mm3. Rashes may occur in 10% of patients. Other side effects include hepatitis, osteomalacia, cardiac conduction defects, and lupus-like reactions. Carbamazepine…: Carbamazepine… Carbamazepine may interact with other drugs by inducing their metabolism. Valproic acid increases concentrations of the 10,11-epoxide metabolite without affecting the concentration of carbamazepine. The interaction of erythromycin and clarithromycin ( CYP3A4 inhibition) with carbamazepine is particularly significant. Loading doses are used only in critically ill patients . Although some patients, especially those on monotherapy, can be maintained on twice-a-day dosing, others may require more frequent administration, especially children. Larger doses can be given at bedtime. Dose increases can be made every 2 to 3 weeks . The sustained- and controlled-release dosage forms allow for twice-a-day dosing. The sustained-release capsule can be opened and sprinkled on food . Ethosuximide: Ethosuximide Ethosuximide is believed to act primarily by inhibition of T-type calcium (Ca) channel . It is a first-line treatment for absence seizures . There is some evidence for nonlinear metabolism at higher doses. Metabolites are believed to be inactive. A loading dose is not required . Titration over 1 to 2 weeks to maintenance doses of 20 mg/kg/day (divided into two doses) usually results in serum concentrations of 50 mcg/mL . Felbamate: Felbamate Felbamate appears to act by blocking N-methyl-D-aspartate responses and by modulating GABAA receptors . It is approved for treating atonic seizures in patients with Lennox-Gastaut syndrome and is effective for partial seizures as well. Because of the reports of aplastic anemia (1 in 3,000 patients) and hepatitis (1 in 10,000 patients), it is now recommended only for patients refractory to other AEDs . Risk factors for aplastic anemia may be a history of cytopenia, AED allergy or toxicity, viral infection, and/or immunologic problems. Gabapentin: Gabapentin Gabapentin inhibits high-voltage activated Ca channels and elevates human brain GABA levels . It is a second-line agent for patients with partial seizures who have failed initial treatment. It may also have a role in patients with less severe seizure disorders, such as new-onset partial epilepsy, especially in elderly patients . Bioavailability decreases with increasing doses . It is eliminated exclusively renally, and dosage adjustment is necessary in patients with impaired renal function . Gabapentin…: Gabapentin… Dosing is initiated at 300 mg at bedtime and increased to 300 mg twice daily on the second day and 300 mg three times daily on the third day. Further titrations are then made. The manufacturer recommends maintenance doses up to 1,800 to 2,400 mg/day , but higher doses (5,000 to 10,000 mg/day) have been used safely. Most clinicians use doses of 2,400 to 4,800 mg/day. Lamotrigine: Lamotrigine Lamotrigine blocks voltage-dependent sodium channels and inhibits high-voltage activated Ca channels . It is useful as both adjunctive therapy for partial seizures and as monotherapy. It may also be a useful alternative for primary generalized seizures , such as absence and as adjunctive therapy for primary GTC seizures. The most frequent side effects are diplopia, drowsiness, ataxia, and headache. Rashes are usually mild to moderate, but Stevens-Johnson reaction has also occurred. The incidence of the more serious rashes appears to be increased in patients who are also receiving valproic acid and who have rapid dosage titration. Valproic acid substantially inhibits the metabolism of lamotrigine . Levetiracetam: Levetiracetam Levetiracetam’s activity may be related to its binding to the synaptic vesicle protein SV2A . Renal elimination of unchanged drug accounts for 66% of drug clearance, and the dose should be adjusted for impaired renal function . The role of therapeutic drug monitoring is unknown . It has linear pharmacokinetics and is metabolized in blood by nonhepatic enzymatic hydrolysis . It is effective in the adjunctive treatment of partial seizures in adults who have failed initial therapy. Levetiracetam…: Levetiracetam… Adverse effects include sedation, fatigue, coordination difficulties, agitation, irritability, and lethargy. A slight decline in red and white blood cells was noted in clinical trials. It is believed to have a low potential for pharmacokinetic drug interactions .??? The recommended initial dose is 500 mg orally twice daily. In some intractable seizure patients, the oral dose has been titrated rapidly over 3 days up to 3,000 mg/day (1,500 mg twice daily). Oxcarbazepine: Oxcarbazepine Oxcarbazepine (a prodrug ) is structurally related to carbamazepine , but it is converted to a monohydrate derivative, which is the active component. It blocks voltage-sensitive sodium channels , modulates the voltage-activated Ca currents, and increases potassium conductance . It undergoes glucuronide conjugation and is eliminated by the kidneys . Patients with significant renal impairment may require a dose adjustment. The half-life (9.3 ± 1.8 hours) is shorter in patients taking enzyme-inducing drugs. The relationship between dose and serum concentration is linear . It does not autoinduce its own metabolism. Oxcarbazepine…: Oxcarbazepine… It is indicated for use as monotherapy or adjunctive therapy for partial seizures in adults and as monotherapy and adjunctive therapy for partial seizures in patients as young as 4 years of age. It is also a potential first-line drug for patients with primary, generalized convulsive seizures . The most frequently reported side effects are dizziness, nausea, headache, diarrhea, vomiting, upper respiratory tract infections, constipation, dyspepsia, ataxia, and nervousness . It generally has fewer side effects than phenytoin, valproic acid, or carbamazepine. Hyponatremia has been reported in up to 25% of patients and is more likely in the elderly. About 25% to 30% of patients who have had a rash with carbamazepine will have a cross-reaction with oxcarbazepine . Oxcarbazepine…: Oxcarbazepine… Concurrent use of oxcarbazepine with ethinyl estradiol and levonorgestrel -containing contraceptives may render these agents less effective . Oxcarbazepine may increase serum concentrations of phenytoin and decrease serum concentrations of lamotrigine (induction of uridine diphosphate glucuronosyltransferase). In adults, the starting dose of oxcarbazepine as monotherapy is 300 mg once or twice daily . This can be increased by 600 mg/day each week to a maximum dose of 2,400 mg/day . This is titrated to the target dose over 2 weeks. In patients converted from carbamazepine, the typical maintenance doses of oxcarbazepine are 1.5 times the carbamazepine dose. Phenobarbital: Phenobarbital Phenobarbital may act by interacting with GABA receptors , blocking high voltage-activated Ca channels , and blocking α-amino-3-hydroxy-5-meth-ylisoxazole-4-propionic acid and kainate receptors . Phenobarbital is the drug of choice for neonatal seizures , but in other situations it is reserved for patients who have failed other AEDs. Phenobarbital is a potent enzyme inducer and interacts with many drugs . The amount of phenobarbital excreted renally can be increased by giving diuretics and urinary alkalinizers . Phenobarbital…: Phenobarbital… The most common side effects are fatigue, drowsiness, and depression. Phenobarbital impairs cognitive performance . In children, hyperactivity can occur. Ethanol increases phenobarbital metabolism , but valproic acid, cimetidine, and chloramphenicol inhibit its metabolism. Phenobarbital can usually be dosed once daily , and bedtime dosing may minimize daytime sedation . Phenytoin: Phenytoin Phenytoin inhibits voltage-dependent sodium channels . Phenytoin is a first-line AED for primary generalized convulsive seizures and for partial seizures . Its place in therapy will be reevaluated as more experience is gained with the newer AEDs. Absorption may be saturable . Absorption is affected by particle size , and the brand should not be changed without careful monitoring . *** Food may slow absorption . The intramuscular route is best avoid ed , as absorption is erratic . Fosphenytoin can safely be administered IV and intramuscularly. Equations are available to normalize the phenytoin concentration in patients with hypoalbuminemia or renal failure. Phenytoin…: Phenytoin… Phenytoin is metabolized in the liver mainly by CYP2C9 , but CYP2C19 is also involved. Zero-order kinetics* occurs within the usual therapeutic range, so any change in dose may produce disproportional changes in serum concentrations . In nonacute situations, phenytoin may be initiated in adults at oral doses of 5 mg/kg/day and titrated upward . Subsequent dosage adjustments should be done cautiously because of nonlinearity in elimination . Most adult patients can be maintained on a single daily dose, but children often require more frequent administration. Only extended-release preparations should be used for single daily dosing. Phenytoin…: Phenytoin… One author suggested that if the phenytoin serum concentration is less than 7 mcg/mL, the daily dose should be increased by 100 mg; if the concentration is 7 to 12 mcg/mL, the daily dose can be increased by 50 mg; and if the concentration is greater than 12 mcg/mL, the daily dose can be increased by 30 mg or less. Common but usually transient side effects are lethargy, incoordination, blurred vision, higher cortical dysfunction, and drowsiness. At concentrations greater than 50 mcg/mL , phenytoin can exacerbate seizures . Chronic side effects include gingival hyperplasia, impaired cognition, hirsutism, vitamin D deficiency, osteomalacia, folic acid deficiency, carbohydrate intolerance, hypothyroidism, and peripheral neuropathy. Phenytoin…: Phenytoin… Phenytoin is prone to many drug interactions. If proteinbinding interactions are suspected, free rather than total phenytoin concentrations are a better therapeutic guide. Phenytoin decreases folic acid absorption , but folic acid replacement enhances phenytoin clearance and can result in loss of efficacy . Phenytoin tablets and suspension contain phenytoin acid , while the capsules and parenteral solution are phenytoin sodium , which is 92% phenytoin. Clinicians should remember that there are two different strengths of phenytoin suspension and capsules . Pregabalin: Pregabalin Pregabalin binds to the subunit of the voltage-gated Ca channel , resulting in a decrease in the release of several excitatory neurotransmitters . It is a second-line agent for partial seizures that have failed initial treatment. It is eliminated primarily by renal excretion as unchanged drug ; dosage adjustment is required in patients with renal dysfunction. The most frequent side effects include dizziness, somnolence, ataxia, blurred vision, and weight gain. Drug interactions are unlikely to occur. It is a controlled substance . Tiagabine: Tiagabine Tiagabine is a specific inhibitor of GABA reuptake into glial cells and other neurons. It is considered second-line therapy for patients with partial seizures who have failed initial therapy. The most frequently reported side effects are dizziness, asthenia, nervousness, tremor, diarrhea, and depression. These side effects are usually transient and can be diminished by taking it with food. It is oxidized by CYP3A4 enzymes, and other drugs may alter its clearance. Tiagabine is displaced from protein by naproxen , salicylates , and valproate . The minimal effective adult dose level is considered to be 30 mg/day. Topiramate: Topiramate Topiramate affects voltage-dependent sodium channels, GABA receptors, high voltage Ca channels , and kainate α-amino-3-hydroxy-5-methylisox-azole-4-propionic acid subunits . It is a first-line AED for patients with partial seizures . It is also approved for tonic-clonic seizures in primary generalized epilepsy . Approximately 50% of the dose is excreted renally , and tubular reabsorption may be prominently involved. The most common side effects are ataxia, impaired concentration, confusion, memory difficulties, dizziness, fatigue, paresthesias, and somnolence. Topiramate…: Topiramate… Nephrolithiasis occurs in 1.5% of patients. It has also been associated with acute narrow-angle glaucoma , oligohidrosis , and metabolic acidosis . Enzyme inducers may decrease topiramate serum levels. Dose increments may occur every 1 or 2 weeks. For patients on other AEDs, doses greater than 600 mg/day do not appear to lead to improved efficacy and may increase side effects. Valproic Acid and Divalproex Sodium: Valproic Acid and Divalproex Sodium Valproic acid may potentiate postsynaptic GABA responses, may have a direct membrane-stabilizing effect, and may affect potassium channels. The free fraction may increase as the total concentration increases, and free concentrations may be more useful than total concentrations, especially at higher concentrations or in patients with hypoalbuminemia. Protein binding is decreased in patients with head trauma. At least 10 metabolites have been identified, and some may be active. One may account for hepatotoxicity (4-ene-valproic acid), and it is increased by concurrent dosing with enzyme-inducing drugs. Valproic Acid and Divalproex Sodium…: Valproic Acid and Divalproex Sodium… It is first-line therapy for primary generalized seizures, such as absence , myoclonic, and atonic seizures, and is approved for adjunctive and monotherapy treatment of partial seizures. It can also be useful in mixed seizure disorders. Side effects are usually mild and include GI complaints, weight gain, drowsiness, ataxia, and tremor. GI complaints may be minimized with the enteric-coated formulation or by giving with food. Thrombocytopenia is common but is responsive to a decrease in dose. Valproic Acid and Divalproex Sodium…: Valproic Acid and Divalproex Sodium… Although carnitine administration may partially ameliorate hyperammonemia , it is expensive, and there are only limited data to support routine supplemental use in patients taking valproic acid. Valproic acid is an enzyme inhibitor that increases serum concentrations of concurrently administered phenobarbital and may increase concentrations of carbamazepine 10,11-epoxide without affecting concentrations of the parent drug. It also inhibits the metabolism of lamotrigine . Twice-daily dosing is reasonable, but children and patients taking enzyme inducers may require three-or-four-times-daily dosing. The enteric-coated tablet divalproex sodium causes fewer GI side effects. It is metabolized in the gut to valproic acid . Zonisamide: Zonisamide Zonisamide is a broad-spectrum sulfonamide AED that blocks voltagesensitive sodium channels by reducing voltage-dependent T-type Ca channels ; it also weakly inhibits carbonic anhydrase, and inhibits glutamate release . It is approved as adjunctive therapy for partial seizures, but it is potentially effective in a variety of partial and primary generalized seizure types. Zonisamide is metabolized primarily by CYP3A4, and about 30% excreted unchanged. The most common side effects include somnolence, dizziness, anorexia, headache, nausea, word-finding difficulties, oligohidrosis, modest weight loss, and irritability. Symptomatic kidney stones may occur in 2.6% of patients . Zonisamide…: Zonisamide… Hypersensitivity reactions may occur in 0.02% of patients, and it should be used with caution if at all in patients with a history of allergy to sulfonamides. Monitoring of renal function may be advisable in some patients. The initial dose in adults is 100 mg/day, and daily doses are increased by 100 mg every 2 weeks until a response is seen. The dosage range in adults is 100 to 600 mg/day. It is suitable for once-or-twice-daily ;;;dosing. EVALUATION OF THERAPEUTIC OUTCOMES: EVALUATION OF THERAPEUTIC OUTCOMES Patients should be chronically monitored for seizure control, side effects, social adjustment, drug interactions, compliance, quality of life, and toxicity. Screening for neuropsychiatric disorders is also important. Clinical response is more important than serum drug concentrations. Patients should be asked to record severity and frequency of seizures in a seizure diary. PowerPoint Presentation: Thank you!! 85

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