Lecture 3-Seizures Disorders and Anticonvulsants (Antiepileptic Agents)

DRUGS USED IN DISORDERS OF THECENTRAL NERVOUS SYSTEM AND TREATMENT OF PAIN Lecture 3: Seizures Disorders and Anticonvulsants Marc Imhotep Cray, M.D. (Antiepileptic Agents) CNS Pharmacology Lecture 3 Learning Objectives: 1. Recognition of the different seizure types 2. The concept that the seizure type determines the selection of a specific antiepileptic drug 3. The spectrum of action of the most commonly used antiepileptic drugs 4.For a given seizure type, an understanding of the selection process of an antiepileptic drug based on its: a) Mechanism of action, b) Efficacy, c) Clinical pharmacokinetics (ease of use), d) Drug-drug interaction potential, e) Tolerability (common side-effects), f) Serious toxicity (idiosyncratic reactions) 5. Role of co-morbidities in selection of an antiepileptic drug Marc Imhotep Cray, M.D. 2 CNS Pharmacology Lecture 3 Classification Schema: Anticonvulsants (Antiepileptic Agents) “Classic” antiepileptic drugs: “Newer” antiepileptic drugs: Benzodiazepines Felbamate (Felbatol) Carbamazepine (Tegretol) Gabapentin (Neurontin) Ethosuximide (Zarontin) Lamotrigine (Lamictal) Phenobarbital Levetiracetam (Keppra) Phenytoin (Dilantin) Oxcarbazepine (Trileptal) Primidone (Mysoline) Pregabalin (Lyrica) Valproic acid Tiagabine (Gabitril) Na Valproate (Depakote) Topiramate (Topamax) Divalproex Na Zonisamide (Zonegran) Marc Imhotep Cray, M.D. 3 CNS Pharmacology Lecture 3 Overview of Epilepsy  Approximately 10% of population will have at least one seizure in their lifetime  Globally, epilepsy is the third most common neurologic disorder after cerebrovascular and Alzheimer’s disease  Epilepsy is not a single entity but an assortment of different seizure types and syndromes originating from several mechanisms that have in common the sudden, excessive, and synchronous discharge of cerebral neurons  Abnormal electrical activity may result in a variety of events, including loss of consciousness, abnormal movements, atypical or odd behavior, and distorted perceptions that are of limited duration but recur if untreated Marc Imhotep Cray, M.D. 4 CNS Pharmacology Lecture 3 Overview of Epilepsy  Site of origin of abnormal neuronal firing determines symptom produced  For example, if motor cortex is involved, patient may experience abnormal movements or a generalized convulsion  Seizures originating in parietal or occipital lobe may include visual, auditory, and olfactory hallucinations  Medications are the most widely used mode of treatment  In general, seizures can be controlled with one medication in approximately 75% of patients  Patients may require more than one medication in order to optimize seizure control  some patients may never obtain total seizure control Marc Imhotep Cray, M.D. 5 CNS Pharmacology ELECTROENCEPHALOGRAPHY Lecture 3  EEG permits recording of collective electrical activity of cerebral cortex as a summation of activity measured as a difference between two recording electrodes  Recording electrodes (leads) are placed on the scalp on at least 16 standard sites, and recordings of potential differences between key electrodes are obtained Marc Imhotep Cray, M.D. 6 CNS Pharmacology Lecture 3 EEG (2) Examples are provided of a 1. normal EEG taken when client is awake with eyes closed and 2. normal EEG sleeping Abnormal patterns of activity can be seen in presence of 3. tumors and 4. seizures Marc Imhotep Cray, M.D. 7 CNS Pharmacology Etiology of Seizures Lecture 3  In most cases, epilepsy has no identifiable cause  Focal areas that are functionally abnormal may be triggered into activity by changes in physiologic factors, such as alteration in blood gases, pH, electrolytes, and blood glucose and changes in environmental factors, such as sleep deprivation, alcohol intake, and stress  The neuronal discharge results from firing of a small population of neurons in a specific area of the brain referred to as the “primary focus”  Neuroimaging techniques, such as magnetic resonance imaging, positron emission tomography scans, and single photon emission coherence tomography, may identify areas of concern Marc Imhotep Cray, M.D. 8 CNS Pharmacology Lecture 3 Etiology of Seizures (2) Intracranial: Marc Imhotep Cray, M.D. 9 CNS Pharmacology Lecture 3 Etiology of Seizures (3) Extracranial: Marc Imhotep Cray, M.D. 10 CNS Pharmacology Lecture 3 Classification of Seizures:  It is important to correctly classify seizures to determine appropriate treatment  Seizures have been categorized by site of origin, etiology, electrophysiologic correlation, and clinical presentation  The nomenclature developed by the International League Against Epilepsy is considered the standard way to classify seizures and epilepsy syndromes  Seizures have been classified into two broad groups: focal and generalized Marc Imhotep Cray, M.D. 11 CNS Pharmacology Lecture 3 A. Focal Seizures (simple, complex)  Involve only a portion of brain, typically part of one lobe of one hemisphere  Symptoms depend on site of neuronal discharge and on extent to which electrical activity spreads to other neurons in brain  Focal seizures may progress to become generalized tonic- clonic seizures Marc Imhotep Cray, M.D. 12 CNS Pharmacology Lecture 3 Focal Seizures, Simple partial:  Caused by a group of hyperactive neurons exhibiting abnormal electrical activity and confined to a single locus in brain  Electrical discharge does not spread, and patient does not lose consciousness or awareness  Pt. often exhibits abnormal activity of a single limb or muscle group controlled by region of the brain experiencing disturbance  Pt. may also show sensory distortions  May occur at any age Marc Imhotep Cray, M.D. 13 CNS Pharmacology Lecture 3 Marc Imhotep Cray, M.D. 14 CNS Pharmacology Lecture 3 Focal Seizures, Complex partial:  Exhibit complex sensory hallucinations and mental distortion  Motor dysfunction may involve chewing movements, diarrhea, and/or urination  Consciousness is altered  Simple partial seizure activity may spread to become complex and then spread to a secondarily generalized convulsion  May occur at any age Marc Imhotep Cray, M.D. 15 CNS Pharmacology Lecture 3 Marc Imhotep Cray, M.D. 16 CNS Pharmacology Lecture 3 B. Generalized Seizures  May begin locally and then progress to include abnormal electrical discharges throughout both hemispheres of brain  Primary generalized seizures may be convulsive or nonconvulsive, and  Patient usually has an immediate loss of consciousness (LOC) Marc Imhotep Cray, M.D. 17 CNS Pharmacology Lecture 3 Generalized Seizures, 1. Tonic-clonic (Grand Mal seizures)  These seizures result in loss of consciousness (LOC), followed by tonic (continuous contraction) and clonic (rapid contraction and relaxation) phases  So-called “Ictal phase”  May be followed by a period of confusion and exhaustion due to depletion of glucose and energy stores  “Postictal phase” Marc Imhotep Cray, M.D. 18 CNS Pharmacology Lecture 3 Marc Imhotep Cray, M.D. 19 CNS Pharmacology Lecture 3 Status Epilepticus- An unbroken cycle of seizures Marc Imhotep Cray, M.D. 20 CNS Pharmacology Lecture 3 Generalized Seizures, 2. Absence (Petit Mal seizures)  These seizures involve a brief, abrupt, and self-limiting loss of consciousness  Onset generally occurs in patients at 3 to 5 years of age and lasts until puberty or beyond  Patient stares and exhibits rapid eye-blinking, which lasts 3 to 5 seconds  Has a very distinct three-per-second spike and wave discharge seen on electroencephalogram Marc Imhotep Cray, M.D. 21 CNS Pharmacology Lecture 3 Marc Imhotep Cray, M.D. 22 CNS Pharmacology Lecture 3 Generalized Seizures, 3. Myoclonic  Consist of short episodes of muscle contractions that may recur for several minutes  Generally occur after wakening and exhibit as brief jerks of limbs  Occur at any age but usually begin around puberty or early adulthood Marc Imhotep Cray, M.D. 23 CNS Pharmacology Lecture 3 Generalized Seizures cont. 4. Clonic: Consist of short episodes of muscle contractions that may closely resemble myoclonic seizures  Consciousness is more impaired compared to myoclonic 5. Tonic: Involve increased tone in extension muscles and are generally less than 60 seconds long 6. Atonic: Also known as drop attacks and are characterized by a sudden loss of muscle tone Marc Imhotep Cray, M.D. 24 CNS Pharmacology Scientific foundations for antiepilepsy Lecture 3 medications screening: ANIMAL MODELS are useful in screening of potential drugs for treatment of epilepsy 1. The convulsant pentylenetetrazol induces convulsions that have drug sensitivities similar to absence seizures 2. Maximal electrical shock induces convulsions with drug sensitivities similar to tonic–clonic seizures 3. Kindling from weak, long-term stimulation of the cortex or amygdala induces generalized seizures  Ref: He XP, Kotloski R, Nef S, et al. Conditional deletion of TrkB but not BDNF prevents epileptogenesis in the kindling model. Neuron, 2004, 43:31–42. Marc Imhotep Cray, M.D. 25 CNS Pharmacology General Mechanism of action (MOA) of Lecture 3 antiepilepsy medications  Drugs reduce seizures through such mechanisms as:  blocking voltage-gated channels (Na+ or Ca2+),  enhancing inhibitory γ-aminobutyric acid (GABA)-ergic impulses and  interfering with excitatory glutamate transmission  Some antiepilepsy medications have multiple targets within the CNS, whereas MOA for some agents is poorly defined Antiepilepsy medications suppress seizures but do not “cure” or “prevent” epilepsy Marc Imhotep Cray, M.D. 26 CNS Pharmacology Lecture 3 Medication selection considerations:  Choice of drug treatment is based on:  Classification of the seizures,  Patient-specific variables (for example, age, comorbid medical conditions, lifestyle, and personal preference), and  Characteristics of the drug (such as cost and drug interactions) o For example, focal-onset seizures are treated with a different set of medications than primary generalized seizures, although the list of effective agents overlaps  Toxicity of agent and characteristics of patient are major considerations in drug selection  In newly diagnosed patients, monotherapy is instituted with a single agent until seizures are controlled or toxicity occurs Marc Imhotep Cray, M.D. 27 CNS Pharmacology Lecture 3 Features Common to Antiepileptics:  Many features are common to most antiepileptics:  None of these drugs are curative  They tend to be highly bound to plasma proteins  They are usually cleared by hepatic metabolism o They may inhibit metabolism of other drugs (valproic acid) o They may induce metabolism of other drugs (e.g., the effectiveness of oral contraceptives can be reduced [phenobarbital, phenytoin, carbamazepine]) o For older “classic” agents, it is important to measure serum anticonvulsant concentration  (Low TI / Low Safety Margin/ Narrow Therapeutic Window) Marc Imhotep Cray, M.D. 28 CNS Pharmacology Lecture 3 Features Common to Antiepileptics (2): Side effects that usually occur include: 1. CNS depression (even phenytoin induces lethargy) 2. Skin rashes (lamotrigine and carbamazepine can cause Stevens– Johnson syndrome, a life-threatening skin condition that is thought to be immune complex mediated) 3. Nystagmus 4. Teratogenicity 5. GI effects (nausea, vomiting) Marc Imhotep Cray, M.D. 29 CNS Pharmacology Lecture 3 First-line Treatments and MOA: Drugs for Treatment of: Mechanism of Action Marc Imhotep Cray, M.D. 30 CNS Pharmacology Lecture 3 First-line Treatments and MOA (2): Drugs for Treatment of: Mechanism of Action Marc Imhotep Cray, M.D. 31 CNS Pharmacology Lecture 3 Unique Features of Individual Agents: Each anticonvulsant has some unique features:  Phenobarbital (Luminal) has a half-life of 4 days  Patients develop some tolerance to sedative–hypnotic effect, but not to antiepileptic effect  Primidone (Mysoline) is an active drug and is also partially metabolized to phenobarbital; thus, it has properties that are very similar to phenobarbital  Phenytoin (Dilantin) is an effective antiepileptic with less sedative activity  Elimination follows zero-order kinetics. After saturation of hepatic enzymes, small increases in dose can lead to large increases in blood concentration  Gingival hyperplasia, megaloblastic anemia, and cardiac arrhythmias are important side effects.  It is often used in new-onset status epilepticus Marc Imhotep Cray, M.D. 32 CNS Pharmacology Lecture 3 Unique Features of Individual Agents (2):  Carbamazepine (Tegretol) is a tricyclic anticonvulsant that has mood stabilization activity  It is also used to treat restless leg syndrome and shingles  It induces MFOs in the liver  Potential side effects liver toxicity, syndrome of inappropriate antidiuretic hormone (SIADH), and aplastic anemia  Oxcarbazepine (Trileptal) is an analog that has less toxicity  Valproic acid (Depakene) is useful for many types of seizures  It can be hepatotoxic, but it does not induce cytochrome P450 enzymes Marc Imhotep Cray, M.D. 33 CNS Pharmacology Lecture 3 Unique Features of Individual Agents (3): Ethosuximide (Zarontin) is the drug of choice for absence seizures  It also does not induce cytochrome P450 enzymes Clonazepam (Klonopin) is a benzodiazepine, which produces considerable sedation  Tolerance can occur with long-term use Tiagabine (Gabitril), levetiracetam (Keppra), and gabapentin (Neurontin) are useful as adjunct therapies for partial seizures  Gabapentin and levetiracetam are also used to treat neuropathic pain Topiramate (Topomax) is useful as an adjunct in treating refractory seizures  Felbamate (Felbatol) can also be used to treat refractory seizures, but they are not first-line therapy due to severe side effects (risk of aplastic anemia (about 1:4000) and hepatic failure.) Marc Imhotep Cray, M.D. 34 CNS Pharmacology Lecture 3 Lamotrigine  Lamotrigine blocks sodium channels, as well as high voltage-dependent calcium channels  Effective in a wide variety of seizure types, including focal, generalized, absence seizures, and Lennox-Gastaut syndrome  Also used to treat bipolar disorder Pharmacokinetics:  Metabolized primarily to the 2-N-glucuronide metabolite through the UGT1A4 pathway  As with other antiepilepsy medications, CYP450 inducers increase lamotrigine clearance leading to lower lamotrigine concentrations, whereas  Divalproex results in a significant decrease in lamotrigine clearance (higher lamotrigine concentrations)  Lamotrigine dosages should be reduced when adding valproate to therapy  Slow titration is necessary with lamotrigine (particularly when adding lamotrigine to a regimen that includes valproate) due to risk of rash, which may progress to a serious, life-threatening reaction Marc Imhotep Cray, M.D. 35 CNS Pharmacology Lecture 3 Status Epilepticus: STATUS EPILEPTICUS is a life-threatening disorder that must be treated rapidly: 1. An intravenous benzodiazepine, such as diazepam (Valium) or lorazepam (Ativan), is the treatment of choice  MOA: Allosterically modulate GABA action at GABAA receptors, which increases frequency of Cl– influx and hyperpolarizes neurons 2. If BDZ is ineffective, other measures must be tried, including:  Phenytoin, given intravenously as fosphenytoin (Cerebyx)  Phenobarbital, given intravenously  General anesthesia Marc Imhotep Cray, M.D. 36 CNS Pharmacology Lecture 3 THE END Marc Imhotep Cray, M.D. 37 CNS Pharmacology Further study (SDL): Lecture 3 MedPharm Digital Guidebook: Unit 3-Drugs Used for CNS Disorders Companion eNotes: CNS- Central Nervous System Pharmacology Textbook Reading: Porter RJ & Meldrum BS. Ch. 24 Antiseizure Drugs In: Katzung BG, ed. Basic & Clinical Pharmacology. 12th ed. Pgs. 403-25 Online resource center: Medical Pharmacology Cloud Folder Lectures/discussions to follow: 4. Antidepressants 5. Antipsychotic Agents 6. Drugs Affecting Bipolar Disorder 7. Drugs Affecting Movement Disorders and Other Neurodegenerative Disorders 8. Analgesics 9. Anesthetics Marc Imhotep Cray, M.D. 38