Anticonvulsants

= Anticonvulsants = ==== Elina and Natalie will work together on this page (This is week #6 readings. Deadline is April 4)

** What is Epilepsy? **
====Makes up a group of disorders that are characterized by periodic and abnormal discharge of nervous tissue. Violent involuntary muscle movements (convulsions) are a characteristic of epilepsy. Also accompanying the convulsions are seizures, which is caused by the abnormal neuronal discharge, which causes electroencephalogram disturbances and other changes in the activity of tissues, receptors, and brain oxygenation. There are many epileptic syndromes that are characterized by different factors, such as cause, seizure type, age of onset, and clinical manifestations.====

** Signs and Symptoms of Seizures: **
====Seizures have many causes and constitute evidence of an underlying neurologic disorder but not a specific disease. Many of the signs and symptoms of these syndromes overlap, so a differential diagnosis of the form of epilepsy can be difficult.====

** Uses of Anticonvulsants: **
====Are being used for some non-seizure disorders such as migraines and bipolar disorder. When anticonvulsants are used to treat pain, they are referred to as “analgesics.” When used to treat bipolar disorders, they are referred to as “mood stabilizers.”====

Seizures are divided into two major groups:
==== 1. Partial Seizures: Convulsions begin in a localized region of the brain, involve restricted areas of the body, are initially unilateral, and yield EEG recordings of rhythmic activity that is restricted t least initially to one hemisphere of the brain. ====

** Generalized Seizures: **
====The most common type of generalized seizure is Tonic-Clonic (Grand Mal), which has a sudden onset. Grand mal epilepsy is greatly responsive to pharmacotherapy. A second common form of generalized seizures is Absence seizure, which characteristically occurs in childhood. The term absence is used due to the brief loss of consciousness and the vacant stare of the patient during the seizure. Absence seizures are also very responsive to pharmacotherapy. Some uncommon types of seizures are myoclonic, characterized by sudden, brief, and violent spasms of one or more muscle groups, and Atonic, which is characterized by a sudden, brief loss of muscle tone. These are often refractory to drug treatment. Generalized seizures occurring in the form of repeated or continuous attacks are referred t as status epilepticus. Status epilepticus may develop in patients who suffer from convulsive disorders, acute disease affecting the brain, after abrupt withdrawal of depressant or anticonvulsant medication, and in rare cases, after the administration of local anesthesia. Drugs that are used commonly to treat status epilepticus are intravenous benzodiazepines such as lorazepam, diazepam, and midazolam. An anesthetic dose of pentobarbital or propofolis effective and has a more rapid onset than Phenobarbital. The large doses that are required increase the chance of respiratory depression and respiratory arrest. Grand mal status epilepticus is best treated in a hospital setting.====

Partial seizures are divided into three broad categories:
==== 1. Simple partial seizure: characterized by seizures that are limited to certain muscles or involving specific sensory changes, psychic symptoms, or autonomic activity. The seizure may remain localized or may spread to contagious brain tissue, causing progressive symptoms as the wave of depolarization makes it’s way along the cerebral cortex. This type of seizure is referred to as Jacksonian epilepsy. ====

2. Complex partial seizure: usually originates in the temporal or frontal lobe, but spreads to broader areas, frequently in a bilateral pattern.
==== 3. The third type is one that progresses to a generalized attack. The initial inciting seizure may be simple or complex. The final clinical result depends on the type of generalized seizure that is triggered. Partial seizures are more refractory to drugs than common generalized seizures. ====

** Secondary Seizures: **
====Seizures may be caused by a fundamental disorder in the ability of the brain to regulate excitation because of genetic causes or abnormal development. Seizures may also occur as a result of another medical condition. Seizures in an otherwise normal individual may occur due to anoxia, metabolic poisons, intoxication, fever, traumatic brain injury, drug use, or systemic administration of local anesthetic overdose. These seizures may resolve after resolution of the underlying cause or may continue if it has resulted in brain injury.====

** Pathophysiology: **
====Characteristics of epilepsies are not very well known. Idiopathic epilepsy has a primary genetic basis, with some influence of environmental factors. The fact that many anticonvulsant drugs are selective for specific seizure types suggests that the origin and progression of all seizures are not identical. Different brain structures may participate as seizure sources. The cortex is often involved. In complex partial epilepsy, unusual activity in the temporal love and limbic structures is found. For absence seizures, changes in the thalamus, basal ganglia, and substantia nigra pars reticulata may be involved. Audiogenic seizures seem to involve the mesencephalon and basal ganglia. In otherwise normal brains, seizures can be initiated by repeated electrical stimulations, a phenomenon called kindling. Individual anticonvulsants often have more than one possible pharmacologic action that may explain their anticonvulsant effect.====

-Benzodiazepines are used in the dental office for the emergency treatment of seizures.
====-Phenobarbital was the first drug used extensively for the treatment of seizures. Other anticonvulsant drugs include hydantoins, succinimides, primidone, carbamazepine, valporic acid, clonazepam, and clorazepate.==== ====-These drugs are sensitive to the spectra of treatment that they should be used for. Prescribing antiepileptic drugs for conditions outside of their spectra can lead to problems much great than just therapeutic failure. For example, absence seizures can be exacerbated by many of the drugs that are used to treat tonic-clonic seizures.====

** Adverse Reactions: **
====-Can result from the direct action of the drug such as dizziness, drowsiness, and ataxia. Adverse reactions can also include withdrawal phenomena, which make the reactions seem paradoxic. Some reactions resemble allergic reactions, which can range from a rash to Stevens-Johnson syndrome. Other adverse reactions can be detected by blood tests. Other adverse reactions are gingival overgrowth, aplastic anemia, hepatotoxicity, renal stones, visual disturbances, and fevers. Anticonvulsant drugs have also been linked to an increased incidence of birth defects.==== ====-Several antiepileptic drugs can alter liver enzyme function. Adverse reactions and drug interactions can result from induction of hepatic enzymes which can alter the metabolism of the inducing anticonvulsant agent, other drugs, altering their half life or toxicity, vitamins, which can produce vitamin deficiencies, and hormones.==== ====-Anticonvulsant drugs can also promote seizure activity or precipitate new seizure types. Some of these drugs include phenytoin, Phenobarbital, vigabatrin, oxycarbazine, lamotrigine, gabapentin, felbamate, and tiagabine.====

** Hydantoins: **
====Phenytoin (diphenylhydantoin) is one of the first drugs to be used for anticonvulsant therapy. This drug was a breakthrough because it suppressed seizures without causing as much of as a sedative affect compared to Phenobarbital. Phenytoin is effective at treating tonic-clonic and partial seizures.====

** Pharmacological Effects: **
====-Even though the mechanism of action is not yet established for the anticonvulsant effect of phenytoin, studies show that phenytoin prevents the spread of abnormal neuronal depolarization from the epileptic focus to surrounding normal neuronal populations. Phenytoin also suppresses the duration of neuronal aftercharge. It may also reduce the spread of neuronal activity and afterdischarge by blocking post-tetanic potentiation.==== ====-The major site of action for phenytoin is at the Na+ channel. Phenytoin delays the neuronal recovery process. Phenytoin binding to the inactivated Na+ increases the voltage required to generate an action potential, which is ideal for anticonvulsant activity.====

-High extracellular K+ also increases the effectiveness of phenytoin.
====-Phenytoin also interferes with Ca++ channels when taken in slightly greater than therapeutic concentrations. Phenytoin interferes with Ca++ channels and the interaction of Ca++ calmodulin, which disrupts Ca++ dependent phosphorylation of proteins necessary for neurotransmitter release from presynaptic nerve terminals.====

Barbituates
** Absorption, Fate, and Excretion ** Phenobarbital is completely absorbed from the gastrointestinal tract. About 30% is excreted unchanged in the urine and the rest is inactivated by the liver. The plasma half life ranges between 50 and 140 hours causing very small fluctuations in plasma concentration over a 24 hour period. Primidone is metabolized to Phenobarbital, which can be detected in plasma in 24-48 hours. ** Adverse Effects ** The most common initial effect of Phenobarbital and other barbitals is sedation. Tolerance also develops. May cause megloblastic anemia and osteomalacia and when given with phenytoin, teratogenicity seems to increase. Most common effects of primidone are CNS depressant and complications include sedation, dizziness, ataxia, and nystagmus, also various blood dyscrasias and rashes. ** CARBAMAZEPINE ** Carbamazepine is a major anticonvulsant drug and is highly effective against tonic-clonic and partial seizures. It also lacks dysmorphic side effects. It is indicated for the treatment of trigeminal neuralgia and other neuropathic pains such as glossopharngeal neuralgia, postherpetic neuralgia, diabetic neuropathy, causalgia, and hemifacial spasms. ** Pharmacologic effects ** Carbamazepine reduces experimentally induced sustained high-frequency neuronal firing at doses that produce clinically relevant plasma concentrations. It also reduces calcium and sodium flux across the neuronal membrane. ** Absorption, Fate, and Excretion ** Carbamazepine is absorbed slowly, reaching peak plasma concentrations in 4-8 hours. It is absorbed though out the body with highest concentrations in the liver, kidneys, and brain. Half life is 25-65 hours and 12 to 17 hours after long-term administration. ** Adverse Effects ** The most common signs and symptoms of overdose are dizziness, diplopia, drowsiness, headache, ataxia, and slurred speech. Convultaions may occure with acute intoxication. Involuntary motor activity and hallucinations and skin rashes, aplastic anemia and agranulocytosis have occurred. ** VALPROIC ACID ** Valporic acid is a broad-spectrum anticonvulsant particularly effective against absence seizures but also useful for other generalized forms of epilepsy and partial seizures. It has also been approved for treatment of mania in bipolar disorder and for migraine pain. ** Pharmacologic Effects **  Valporic acid reduces sustained high frequency neuronal firing at therapeutic doses. It binds to a different site on the Na+ channel. It increases brain GABA by stimulating glutamic acid decarboxylase. It also has the ability to inhibit Ca+ influx through T-type Ca++ channels. ** Absorption, Fate and Excretion ** Valporic acid is completely absorbed form the gastrointestinal tract and is highly bound to plasma proteins. Food may delay absorption. It undergoes complex oxidation and conjugation before excretion in the urine. The half life of valporic acid is approximately 5-20 hours with peak blood concentrations at 1-4 hours. ** Adverse Effects ** sedation, weakness, ataxia, gastrointestinal disturbances, weight gain, hepatotoxicity (especially in children 2yrs or less) spina bifida if given during pregnancy, visual disturbances, pancreatitis, hyperammonemia. ** SUCCINIMIDES ** Ethosuximide is a major drug for the treatment of absence seizures. It is rarely used today because of its toxicit ** Pharmacologic Effects ** Ethosuximide prevents seizures in approximately 50% of patients and reduces their frequency 40-45%. The mechanism of action is not fully established. ** Absorption, Fate, and Excretion ** Succinimides are absorbed from the gastrointestinal tract, metabolized in the liver, and excreted as metabolites in the urine. The ethosuximide half life is approximately 30 hours in children and 45-60 hours in adults. ** Adverse Effects ** Succinimides commonly cause gastrointestinal distress, headache, dizziness, and skin rash. Patients with hematopoietic toxicity may exhibit fever, sore throat, and coagulopathy, as indicated by oral and cutaneous petechiae. Ethosuximide is preferred in pregnancy.

** DRUGS AFFECTING Y-AMINOBUTYRIC ACID TRANSMISSION ** ** BENZODIAZEPINES ** Most benzodiazepines agonist have anticonvulsant properties. Diazepam, clonazepam, clorazepate, midazolam, and lorazepam are the principal benzodiazepines used clinically in the United States as aniticonvulsants. Adverse reactions include drowsiness (if unwanted, since some anxiety results in insomnia and so drowsiness is a benefit), in coordination, confusion, ataxia (loss of muscle coordination), dysarthria (problems with speech and articulation such as stuttering or stammering, caused by nerve defects), apathy, muscle weakness, dizziness, and somnolence (induces sleep). Elderly and young patients experience excitement instead of depression (paradoxic reactions): nightmares, hyperactivity, insomnia, irritability, agitation, rage, and hostility, and also causes changes in sleep patterns. Allergic reactions can result; these are usually rashes on the skin. It should be limited during pregnancy. Nitrazepam is not available in the United States. ** VIGABATRIN ** <span style="color: black; font-size: 12pt; margin-bottom: 10pt; margin-left: 0in; margin-right: 0in; margin-top: 0in;">Vigabatrin is an irreversible inhibitor of the enzyme GABA transaminase. Vigabatrin is considered and adjunctive anticonvulsant and is effective for drug-refactory epilepsy. It is more effective for simple and complex partial seizures than for generalized seizures. It is rapidly absorbed by the oral route, reaching peak blood concentrations in 0.75 to 2 hours. It does not bind appreciably to plasma protein. It has no active metabolites and is excreted by the kidneys. Its plasma half life is 4-7 hours. Adverse effects include sedation, fatigue, weight gain, amnesia, and visual field defects. Effects may be more common in men and seem to be related to total drug exposure. They persist after drug withdrawal and psychosis may occur infrequently. ** TIAGANIBE ** <span style="color: black; font-size: 12pt; margin-bottom: 10pt; margin-left: 0in; margin-right: 0in; margin-top: 0in;">Tiagabine is an adjunct for refractory complex epilepsy, is a nipecotic acid derivative that inhibits GABA uptake. It is readily absorbed with a peak blood concentration reached in 45 minutes, it is metabolized by the liver, and has a half life of 7-9 hours. Side effects include dizziness, fatigue, sleepiness, nausea, tremor, and difficulty concentrating. ** NEUROSTEROIDS ** <span style="color: black; font-size: 12pt; margin-bottom: 10pt; margin-left: 0in; margin-right: 0in; margin-top: 0in;">Steroid hormones are generally thought to act through steroid nuclear binding proteins tha modify DNA translation in the cell nucleus. ** MISCELLANEOUS ANTICONVULSANTS ** ** GABAPENTIN AND RELATED DRUGS ** <span style="color: black; font-size: 12pt; margin-bottom: 10pt; margin-left: 0in; margin-right: 0in; margin-top: 0in;">Gabapentin is a GABA analogue specifically designed to cross the blood-brain barrier. It is effective as an adjunct for patients with refactory partial seizures. Gabapentin is ineffective in the treatment of absence seizure, but has proved useful in the treatment of chronic pain conditions, such as postheraputic neuralgia, diabetic neuropathy, trigeminal neuralgia, and pain associated with multiple sclerosis. The drug is used orally and has saturable absorption and is excreted almost entirely by the kidneys and has a plasma half life of 4-7 hours. Adverse effects include fatigue, dizziness, headache, nausea, and ataxia. ** GABAmimetic Agents ** <span style="color: black; font-size: 12pt; margin-bottom: 10pt; margin-left: 0in; margin-right: 0in; margin-top: 0in;">Progabide is a GABA antagonist that successfully mimics GABA. It is effective in some forms of epilepsy, but can cause serious adverse effects. ** FELBAMATE ** <span style="color: black; font-size: 12pt; margin-bottom: 10pt; margin-left: 0in; margin-right: 0in; margin-top: 0in;">Felbamate is a meprobamate derivative used in refractory partial seizures associated with Lennox-Gastaut syndrome, a disease resistant to most antiepileptic drugs. Serious risks for the patient. ** LAMOTRIGINE ** Lamotrigine is a phenyltriazine derivative that inhibits sodium influx in rapidly firing neurons. It exerts anticonvulsant effects in several experimental models of epilepsy and in patients with partial and generalized tonic-clonic seizures. Also used to treat mania. The drug is taken orally and is absorbed from the gastrointestinal tract with a plasma half life of approximately 24 hours. Mild side effects include ataxia, dizziness, diplopia, and rash. Steven Johnson syndrome has been reported in children. ** CARBONIC ANHYDRASE INHIBITORS ** Primarily effective against absence seizures. Tolerance is developed rapidly. ** TOPIRAMATE ** Topiramate is a broad-spectrum anticonvulsant for partial onset seizures, monotherapy, tonic-clonic seizures, treatment of Lennox-Gastaut syndrome, and prophylaxis of migraine headaches. It is orally ingested and is absorbed rapidly with a half life of approximately 20 hours. CNS depression is the most common side effect and may compromise short term memory. ** ZONISAMIDE ** Zonisamide is structurally related to sulfonamides. It is completely absorbed with peak concentrations occurring at 4-6 hours. It is primarily metabolized by CYP3A4. It may produce allergic reactions to those who are sensitive to sulfonamides. Allergic reactions include skin rashes, Stevens- Johnson syndrome, epidermal necrolysis, and agranulocytosis. Other side effects include renal acidification and renal stones, and rarely dehydration and hyperthermia in children during hot weather. ** LEVETIRACETAM ** Levetiracetam is a pyrrolidine derivative that is rapidly absorbed after oral administration. The half life is approximately 7 hours and the drug is metabolized by a non-cytochrome P450 route and is eliminated by renal excretion. It was found to reduce seizures in a dose-dependant manner and is also approved for treatment of myoclonic epilepsy. Side effects include somnolence and fatigue, Coordination difficulties, and exacerbation of behavioral problems. ** MAGNESIUM SALTS ** Not used in treating epilepsy but is used to prevent or control convulsions of eclampsia and sever preeclampsia of pregnancy. It acts on CNS to decrease excitability and to reduce activity at the neuromuscular junction. It also reduces cardiac and smooth muscle activity and reduces blood pressure. ** NONPHARMACOLOGIC TREATMENT ** Surgical treatment of seizures can be done when it is localized and located in nonessential brain tissue. Vagal stimulation is stimulation of the vagus nerve to block experimentally induced seizures. Another treatment for epilepsy is a ketogenic diet which is high in fats and low in carbohydrates and proteins. ** GENERAL THERAPUTIC USE ** The goal is to control epileptic seizures with the least amount of drugs, toxicity, and dose. Anticonvulsants can also treat patients with various chronic pain problems and the manic phase of bipolar disorder. ** IMPLICATIONS FOR DENTISTRY ** One of the best ways to manage seizures is to prevent them by planning appointments at times when an epileptic patient has high blood concentrations of anticonvulsant medication. Also asking the patient if they took their meds before the appointment and paying careful attention to local anesthetic doses. An emergency plan should include anticonvulsant medications and should be administered the intravenous route such as midazolam. Side effects should be noted such as CNS depression and gingival overgrowth, especially in mouth breathers. A patient should be treated with caution to prevent emotional upset that can trigger a seizure. Anticonvulsants may be used to treat orofacial pain problems.