EpilepsyPharmacotherapy 3 Fall semester 2012-2013

References:

• DiPiro Ch 65: Epilepsy

• Koda-Kimble Ch 58: Seizure disorders

Definitions

• Epilepsy is a disorder due to disturbed electrical activity in the brain, which may have many etiologies.

• It is a collection of many different types of seizures that vary widely in severity, appearance, cause, consequence, & management.

• Seizures that are prolonged or repetitive can be life-threatening.

• Epilepsy is defined by occurrence of at least 2 unprovoked seizures separated by 24 hours

Incidence, Prevalence, & Epidemiology

~ 10% of the population have a seizure at some time.

Causes: meningitis, trauma, tumors, exposure to toxins - may become recurrent & require chronic treatment with antiepileptic drugs (AEDs).

Reversible conditions: alcohol withdrawal, fever, metabolic disturbances may cause isolated seizures that usually do not require long-term AED therapy.

If no underlying cause=idiopathic epilepsy

Classification of Seizures & Epilepsies

An epileptic seizure is the “clinical manifestation that results from abnormal & excessive discharge of a set of neurons in the brain”.

Clinical manifestations: sudden & transitory abnormal phenomena that may include alterations of consciousness, motor, sensory, autonomic, or psychic events perceived by the patient or observer.

Epilepsy is a “condition characterized by recurrent (≥2) epileptic seizures, unprovoked by any immediate identified cause.”

Epileptic syndromes

• Seizures can be described as epileptic syndromes that may include cause (if known), precipitating factors, age of onset, characteristic EEG patterns, severity, chronicity, family history, & prognosis.

Nonpharmacologic Treatment

• Surgery: up to 90% of patients may improve or become seizure free. In epileptic syndromes such as Lennox-Gastaut syndrome may prevent or lessen neurologic deterioration & developmental delay

• Ketogenic diet (low-carbohydrate, high- fat): for patients who cannot tolerate AEDs or for seizures that are not completely responsive to AEDs: persistent ketosis, which is believed to play a major role in therapeutic effect. Most commonly used & seems to be most beneficial in children

• Vagus nerve stimulator for treatment of intractable partial seizures

• Avoiding of precipitating factors (stress, sleep deprivation, ingestion of excessive amounts of caffeine or alcohol)

Antiepileptic Drug (AED) Therapy

• If a decision is made to start AED therapy, monotherapy is preferred, & ~ 50-70% of all patients can be maintained on 1 drug.

• However, many of these patients are not seizure free. • After 12 months of treatment, 48-55% of patients with

only GTC seizures are seizure-free, but only 23–26% of those with CP seizures are seizure-free.

• Of 35% of patients with unsatisfactory control, 10% will be well controlled with 2-drug treatment.

• Of the remaining 25%, 20% will continue to have unsatisfactory control despite multiple drug treatment.

• Some of these patients may become candidates for surgery or vagal nerve stimulator

When to start AEDs?1. Some clinicians start AED treatment after 1st seizure, 2. Others do not initiate treatment until 2nd, unprovoked

seizure. 3. Others initiate prophylactic treatment following CNS insult

that may cause epilepsy (e.g., stroke or head trauma). • In single isolated seizure, 1 of 3 decisions can be made:

treat, possibly treat, or do not treat. • If no risk factors, probability of 2nd seizure is < 10% in 1st

year. If risk factors are present, recurrence rate can be 80% after 5 years.

• Decision on whether to start AED therapy often depends on patient-specific factors such as epilepsy syndrome, seizure etiology, presence of a neuroanatomic defect, EEG, patient's lifestyle & preferences.

• Patients who have had 2 or > seizures generally should be started on AEDs

Epilepsy management algorithm

When to stop AEDs?

• AED withdrawal generally is not suggested for patients with juvenile myoclonic epilepsy, absence with clonic-tonic-clonic seizures, or clonic-tonic-clonic seizures.

• American Academy of Neurology (AAN) guidelines for discontinuing AEDs in seizure-free patients (1996): AED withdrawal can be considered in a patient meeting the following profile:

1. - seizure free for 2-5 years, 2. - history of single type of partial seizure or primary

GTC seizures, 3. - normal neurologic exam & normal IQ, 4. - EEG normalized with treatment.

When to stop AEDs? (cont’d)

• AED withdrawal should be done gradually, especially in patients with profound developmental disabilities.

• Some patients will have a recurrence of seizures as AEDs are withdrawn.

• Sudden withdrawal is associated with precipitation of status epilepticus, particularly with Barbs & BDZs

• Seizure relapse has been reported to be more common if these AEDs are withdrawn over 1 to 3 months compared to over 6 months.

Therapeutic end points

• Careful titration of doses is needed to achieve seizure control

• It may not be possible to completely prevent seizures without producing intolerable adverse effects.

• A balance between efficacy & side effects must be reached because with older AEDs used as monotherapy, fewer than 50% of patients become seizure-free

• → therapeutic end points actually achieved will vary among patients

Serum drug concentrations (TDM)

• Individual patients differ in their response to a particular serum drug concentration → “therapeutic” serum concentrations should be considered only as guidelines for treatment.

• Seizure type, how many seizures occur before control is achieved, may significantly influence serum drug concentrations required for seizure control.

• Eg, complete control of simple or complex partial seizures requires serum concentrations of carbamazepine (Tegretol) 27% higher than those needed for complete control of generalized tonic-clonic seizures;

• Many patients may be controlled with serum drug concentrations below “therapeutic” range.

Measurement of serum drug concentrations may be useful in:

• Uncontrolled seizures despite administration of greater-than-average doses: distinguish drug resistance from subtherapeutic drug concentrations caused by malabsorption, noncompliance, or rapid metabolism.

• Seizure recurrence in a previously controlled patient: often is due to noncompliance

• Documentation of intoxication: in patients who develop signs or symptoms of dose-related AED toxicity

Measurement of serum drug concentrations…(cont’d):

• When patients are receiving multiple AEDs, serum concentrations of all drugs should be measured following change in dose of one drug (changes in serum concentration of one drug frequently change pharmacokinetic disposition of other drugs.

• When precise dosage changes are required: On occasion, small changes in dose of a drug (e.g., phenytoin) may result in large changes in both serum concentration & clinical response.

Factors that may alter relationship between AED serum concentration &

response to drug• Pharmacokinetic factors• Laboratory variability (10% error)• Therapeutic ranges are not well established for

many drugs eg valproate, lamotrigine• Inappropriate sampling timing• Protein binding: Determination of serum

concentrations of free (i.e., unbound) AEDs is available from many commercial laboratories; these determinations are expensive & results may not be available for several days.

Obtaining samples for TDM

• Generally, serum concentrations of AEDs should not be measured until min. 4-5 t1/2 have elapsed since initiation of therapy or a dosage change.

• Blood samples should be obtained in the morning, before any doses of AED have been taken; (i.e., “trough”) serum concentrations.

• On occasion, especially for rapidly absorbed drugs with short t1/2 (e.g., valproate), determination of peak serum concentrations may help assess possible toxic symptoms.

Monotherapy vs polytherapy

• Monotherapy at optimal tolerated serum concentrations produces excellent therapeutic results & minimal side effects in up to 65-70% of patients. Most experts advocate use of monotherapy whenever possible.

• Addition of second AED significantly improves seizure control in only 10-20% of patients.

• Polytherapy should be reserved for patients with multiple seizure types or for patients whom first-line AEDs have failed to control seizures when titrated to maximum tolerated doses

AEDs ADRs

Carbamazepine: monitoring

• CBCs should be obtained before therapy & at monthly intervals during the first 2-3 months of therapy; thereafter, a yearly or every-other-year CBC.

• Hepatic adverse reactions are idiosyncratic. Alkaline phosphatase & y-glutamyl-transferase (GOT) concentrations often are elevated in patients taking carbamazepine due to hepatic enzyme induction

• Patients should be aware that the appearance of unusual symptoms (e.g., jaundice, abdominal pain, excessive bruising/bleeding, or sudden onset of severe sore throat with fever) should be reported to a health care professional.

Active metabolite of carbamazepine

• Carbamazepine’s active metabolite, carbamazepine-10,11-epoxide (CBZ-E), may result in increased seizure activity without other symptoms of intoxication in some patients despite usual serum concentrations of parent compound.

• This is most likely to occur in patients receiving other drugs (usually valproate & felbamate) that inhibit metabolism of CBZ-E. Mental retardation also may be predisposing factor for this form of intoxication.

Carbamazepine-induced hyponatremia

• Is associated with syndrome of inappropriate antidiuretic hormone (SIADH): headache, N&V, dizziness; in more severe cases, confusion & increased seizure activity-may be mistakenly attributed to carbamazepine intoxication.

• Can be treated by dosage reduction & mild fluid restriction.

• Discontinuation of carbamazepine & substitution of alternative AED may be necessary.

• Demeclocycline (Declomycin) has been used successfully: inhibits activation of ADH-sensitive adenyl cyclase in distal renal tubules & collecting ducts.

• Some patients may respond to ↑ Na intake.

Phenytoin: pharmacokinetics

• Dose-dependent (Michaelis-Menten or capacity-limited) pharmacokinetic

• Apparent half-life of phenytoin changes with dose & serum concentration→

• time required to reach new steady state after alteration in dosage is difficult to predict because it depends on dosage itself & patient’s pharmacokinetic parameters

• Alterations in phenytoin dosage before steady state (may take up to 90 days) has been reached may result in significant fluctuations in serum concentrations & patient’s clinical status

Phenytoin oral loading dose

• Practical approach with lower risk of complications involves giving 1.5-2 times prescribed maintenance dose for the first 2-3 days of treatment.

• Serum phenytoin concentrations should be checked on the day after completion of such a “miniloading” & weekly thereafter.

Fosphenytoin

• Phosphate ester prodrug of phenytoin, is highly water soluble.

• Is administered parenterally (IM or IV) without need for solubilization using propylene glycol or adjustment of pH to non-physiologic levels.

• Causes less risk of tissue damage & venous irritation than with parenteral administration of phenytoin.

• Is rapidly absorbed & converted to phenytoin by phosphatase enzymes.

Phenytoin ADRs

1. Gum hyperplasia• treatment of existing hyperplasia: (1) dosage

reduction or replacement of phenytoin with an alternative AED; (2) surgical gingivectomy will correct the problem temporarily; (3) oral physiotherapy (periodontal treatment) eliminates local irritants & maintains oral hygiene.

2. Neurotoxicity • chronic intoxicating doses of phenytoin: risk for

irreversible cerebellar damage or peripheral neuropathy - dysarthria, ataxic gait, intention tremor, & muscular hypotonia

Coarsening of Facial Features

HW:

• Effect of AEDs on the bone & its management (DiPiro, Koda-Kimble)

ADRs of new AEDs: Felbamate

• Due to risk of aplastic anemia & hepatic failure routine hematologic studies & LFTs should be performed

• Patients & their families should be fully informed of potential risks. Written consent is recommended.

• Patients must be educated about symptoms of hematologic & hepatic toxicity.

• Place of felbamate in treatment of epilepsy is uncertain.

ADRs of new AEDs…cont’d

• Topiramate may cause cognitive disturbances, lethargy, & impaired mental concentration in large doses

• Topiramate causes nephrolithiasis due to inhibition of carbonic anhydrase, with resulting increased urinary pH & decreased citrate excretion.

• Topiramate may also cause weight loss.• Gabapentin, tiagabine, & levetiracetam have

not been associated with serious side effects; tiagabine has caused nonspecific dizziness

ADRs of new AEDs…cont’d

• The most serious ADR of lamotrigine is skin rash

• It may progress to erythema multiforme or toxic epidermal necrolysis.

• Lamotrigine-related rashes may resolve rapidly when lamotrigine is discontinued.

• Coadministration of valproate may increase the likelihood of skin reactions;

Erythema multiforme & toxic epidermal necrolysis

ADRs of new AEDs…cont’d

• Oxcarbazepine, derivative of carbamazepine, is prodrug for monohydroxy active metabolite.

• Oxcarbazepine causes less frequent, less severe ADRs compared with carbamazepine because it is not converted to 10,11-epoxide metabolite.

• Zonisamide is sulfonamide derivative & thus is contraindicated in patients allergic to sulfonamides. Kidney stones have developed in 3% to 4% of patients.

Drugs for absence seizures

• First choice: ethosuximide• Valproate is more likely to cause nausea &

drowsiness, it is more expensive than ethosuximide, & is more likely to interact with other AEDs.

• Valproate usually is reserved for patients whose absence seizures do not respond to ethosuximide.

• Clonazepam, a benzodiazepine, often is effective but use is limited by prominent CNS side effects (sedation, ataxia, mood changes) & development of tolerance

Valproate: hepatotoxicity

• Is caused by accumulation of directly hepatotoxic metabolites (probably 4-en-valproate) formed in larger quantities in patients who also receive enzyme-inducing drugs such as phenobarbital.

• Most cases of fatal hepatotoxicity have occurred in young (<2 years old) patients with neurologic & metabolic abnormalities who also suffered from severe, difficult- to-control seizures and who were taking multiple AEDs.

Valproate: hepatotoxicity…cont’d

• Asymptomatic elevations in liver enzymes occur commonly during the first 6 months of treatment with valproate & usually are not associated with severe hepatotoxicity.

• frequent LFTs during early valproate therapy are unlikely to detect serious hepatotoxicity

• Education of caregivers &/or patients regarding potential symptoms of hepatotoxicity, with careful observation & follow-up by health care professionals, is recommended as the most effective method for monitoring

• Especially careful monitoring should be provided for predisposed patients

• Other ADRs: tremor & thrombocytopenia

Skin rash as ADR of AEDs

• Is relatively common (2-3% of patients) side effect related to AED therapy.

• It is most commonly associated with phenytoin, lamotrigine, carbamazepine, & phenobarbital.

• Most cases are relatively mild, but severely affected patients may develop Stevens-Johnson syndrome &/or systemic hypersensitivity syndrome with severe hepatic damage.

• Viral infection (e.g., hepatitis, influenza, infectious mononucleosis) should be considered & ruled out

• Reactive epoxide metabolites (arene oxides) of phenytoin (& other chemically similar AEDs) are causative agents.

Skin rash as ADR of AEDs…cont’d

• Genetic predisposition to hypersensitivity, possibly because of relative deficiency of epoxide hydrolase enzymes

• Carbamazepine, phenytoin, & phenobarbital all are metabolized by similar pathways & converted to reactive arene oxides.

• Carbamazepine-induced liver damage also may result from effects of accumulation of reactive epoxide metabolites; these reactive metabolites are different from 10,11 -epoxide metabolite

Drug interactions

Interaction between phenytoin & valproate

1. Valproate displaces phenytoin from binding sites on serum albumin →↑ free fraction of phenytoin.

• For some patients, there is no net clinical effect because metabolism of phenytoin ↑ & free serum conc. of phenytoin return to their predisplacement levels → total serum phenytoin conc. would be ↓ while free fraction remain ↑.

• If serum conc. of phenytoin is high enough → saturation of metabolic enzymes, unbound conc. of phenytoin may remain ↑ & total serum phenytoin conc. may change only slightly or even ↑.

Interaction between phenytoin & valproate…cont’d

2. Valproate also is capable of inhibiting metabolism of phenytoin →↑ both unbound & total serum phenytoin conc.

• Clinical status of patient must be monitored carefully; determination of free (unbound) serum phenytoin conc. may be helpful

3. Stimulation of valproate metabolism by phenytoin. During concomitant therapy, larger doses of valproate will be required to achieve effective seizure control.

Valproate-carbamazepine interaction

• Serum concentrations of valproate in patients receiving carbamazepine may be only approximately 50% of those expected

• Valproate may inhibit epoxide hydrolase & cause accumulation of CBZ-E sufficient to exert significant pharmacologic effects

• Initial decrease of 10% to 20% (200 mg) of daily carbamazepine dose would be reasonable.

• Subsequently, carbamazepine dose can be tapered using reductions of 200 mg every 1 to 2 weeks monitoring patients for increased seizure activity.

Rectal diazepam gel (Diastat)• Is available for home administration to patients

with acute episodes of repetitive seizure activity. • It is absorbed relatively rapidly & it is often

effective in terminating cluster seizures within 15 minutes or less.

• Use of diazepam rectal gel is recommended only when caregivers can recognize onset of cluster seizures, & when caregivers can be trained to administer preparation safely & to monitor patient’s response (e.g., respiratory status)

• Caregivers should be informed that this preparation is not for PRN use with every seizure

Febrile seizures

• Up to 5% of children have febrile seizure between 6 months & 6 years of age.

• Simple febrile seizures occur with fever of ≥38°C in previously normal children <5 years of age. They last <15 minutes & have no focal features. Associated seizure does not arise from CNS pathology.

• Complex febrile seizures show focal characteristics or are prolonged. Child may or may not have previous neurologic abnormalities.

• Febrile status epilepticus consists of continuous or serial tonic-clonic seizures lasting >30 minutes without return of consciousness.

Febrile seizures…cont’d

• Risk of occurrence of febrile seizures following 1 or > febrile seizures is 2-3 times greater than in general population.

• risk factors associated with later development of chronic epilepsy are:

1. family history of febrile seizures, 2. complicated initial seizure, 3. pre-existing neurologic abnormality

Prophylaxis & treatment of febrile seizures

• Immediate antiepileptic therapy is not required. • Measures to reduce elevated temperature

should be initiated immediately to reduce risk of further seizures: acetaminophen & tepid sponge baths.

• In prolonged or repeated febrile seizures, either phenobarbital or diazepam may be administered

• Prevention: only early age (<1 year) at first febrile seizure & family history of febrile seizures reliably predicted significant increase in risk of repeat febrile seizures.

Prophylaxis & treatment of febrile seizures…cont’d

• AED prophylaxis should be considered only when multiple risk factors or other medical conditions that place patient at special risk are present.

• Complex febrile seizures or febrile status epilepticus should be treated with chronic AED therapy

• Early antipyretic therapy may help prevent further febrile seizures.

• Intermittent administration of oral diazepam (Valium) at onset of febrile illness also can be of value: 0.33 mg/kg PO Q 8 hours → discontinued 24 hours after last seizures

Prophylaxis & treatment of febrile seizures…cont’d

• No evidence supports that medication will significantly affect later development of epilepsy.

• Phenobarbital & valproate are the only AEDs that have been considered useful for febrile seizure prophylaxis, & even their efficacy is being seriously questioned.

• Phenobarbital’s use for this purpose is difficult to justify when one considers risk of learning impairment.

• Phenobarbital therapy is associated with hyperactivity & behavioral disturbance in up to 75% of children

Women’ issues in epilepsy

• There have been several reports of reduced efficacy of oral contraceptives by AEDs: phenobarbital, phenytoin, carbamazepine, oxcarbazepine, & felbamate (↑metabolism of ethynylestradiol & progestogens)

• Topiramate in polytherapy & at high dosages has mild effect on oral contraceptive pharmacokinetics

• Second contraceptive method (e.g., condoms, intrauterine devices, or spermicide) is recommended to avoid contraceptive failure

Teratogenicity• Limited experience regarding teratogenic

potential of lamotrigine, felbamate, gabapentin, topiramate, tiagabine, levetiracetam, oxcarbazepine, & zonisamide.

• Risk of major congenital malformations (e.g., facial clefts, cardiac septal defects) in children exposed to AEDs in utero may be twice times baseline risk in general population.

• Many of these teratogenic effects can be prevented by adequate folate intake; therefore, prenatal vitamins with folic acid (~0.4–5 mg/day) should be given to any woman of child-bearing potential who is taking AEDs. Higher folate doses should be used in women with history of previous pregnancy with neural tube defect.

Craniosynostosis from valproate

Effect of pregnancy on AEDs

• During pregnancy, serum levels of AEDs (including free serum levels for highly protein-bound drugs) should be monitored.

• Dosage adjustments may aid in preventing increased seizure frequency seen in ~25% of pregnant women with epilepsy.

Vitamin K Supplementation

• Babies born to women with epilepsy who are taking enzyme-inducing AEDs (carbamazepine, phenobarbital, primidone, &/or phenytoin) are at risk of hemorrhage due to decreased vitamin K—dependent clotting factors.

• Women should receive vitamin K 20 mg every day from 36 weeks of gestation until delivery, & babies should also receive vitamin K I mg IM at birth

Breast-feeding

• For majority of the first-generation AEDs (carbamazepine, phenytoin, valproic acid), breast-feeding results in negligible plasma concentrations in the infants.

• For second-generation AEDs, breast-feeding should be done cautiously & the infant should be monitored for excess AED plasma concentrations & toxicity, if possible.

Status epilepticus (SE)

• exists if there is “more than 30 minutes of (I) continuous seizure activity or (2) two or more sequential seizures without full recovery of consciousness between seizures

• SE also may be characterized by nonconvulsive seizures that produce a persistent state of impaired consciousness or by partial seizures (motor or sensory that may not interfere with consciousness)

Status epilepticus (SE)…cont’d• Uncontrolled convulsive SE may cause severe

metabolic & hemodynamic alterations. • Prolonged, severe muscle contractions & CNS

dysfunction from uncontrolled seizure discharges result in hyperthermia, cardiorespiratory collapse, myoglobinuria, renal failure, & neurologic damage.

• Neurologic damage also may occur with nonconvulsive SE; neurologic sequelae of SE are related to excessive electrical activity & resulting alterations in brain metabolism.

• After 30 minutes of seizure activity, body often fails to compensate for increased metabolic demands, & cardiovascular collapse may occur.

• Mortality in adults with SE may be 30%

Treatment of SE

• Immediate therapeutic concern is to ensure ventilation & terminate current seizure activity.

• If possible, airway should be placed; however, this may not be possible while patient is convulsing.

• Objects (e.g., spoons, tongue blades) should never be forced into mouth of seizing patient.

• If airway placement is impossible, patient should be positioned on his side to allow drainage of saliva & mucus from mouth & prevent aspiration.

Treatment of SE…cont’d

• IV line should be established using normal saline, blood should be obtained for serum chemistries (especially glucose & electrolytes), AED serum concentrations, & toxicology screens.

• Thiamine 100 mg or vitamin B complex should be given IV.

• This should be followed by 25 g of glucose (50 mL of 50% dextrose solution) by IV push; these measures will correct any hypoglycemia, which may be responsible for SE.

Treatment of SE…cont’d

• Lorazepam (Ativan) or diazepam (Valium) → phenytoin (Dilantin) or fosfenytoin (Cerebyx)

• Lorazepam works for 72 hours• IV phenobarbital is usually reserved for use in

cases of SE that do not respond to benzodiazepines & phenytoin.

• Phenytoin & fosphenytoin are indicated for treatment of SE, but owing to limitations on their rates of infusion, onset of their peak effect may be delayed → usually used following initial treatment with lorazepam or diazepam.

Treatment of SE…cont’d

• Lorazepam may cause significant venous irritation, should be diluted with equal volume of normal saline solution or water for injection before IV administration.

• Doses of either lorazepam or diazepam should be repeated after 5-10 minutes if seizure activity has not stopped.

• Both lorazepam & diazepam are relatively safe drugs. Their primary adverse effects are sedation, hypotension, & respiratory arrest (usually short-lived)

Treatment of SE…cont’d

• IV phenytoin can be administered by direct injection into running IV line. Cardiovascular status (BP, electrocardiogram) should be monitored closely during administration.

• If fosphenytoin is administered, it can be given by either direct IV injection or, after dilution in any suitable IV solution, by infusion

• Absence of propylene glycol as diluent renders fosphenytoin potentially less likely than phenytoin to cause cardiovascular adverse effects (HW: What are they?)

• Pruritus & paresthesias are common side effects during IV fosphenytoin administration (due to phosphate component).