What is epilepsy? Epilepsy “seizure disorder” is a syndromic disease characterized by disorder of the brains electrical system. Abnormal electrical impulses cause brief changes in movement, behaviour, sensation, or awareness. These interruptions, known as seizures, may last from a few seconds to a few minutes. People who have had two or more seizures are considered to have epilepsy.
What is seizure? Time-limited paroxysmal events that result from abnormal, involuntary, rhythmic neuronal discharges in the brain Seizures are usually unpredictable and brief ( < 5 minutes) and stop spontaneously
Etiology of epilepsy Any process that alters the structure or the function of the brain neurons can cause epilepsy Processes that lead to structural alteration include; Congenital malformation Degenerative disease Infectious disease Trauma Tumors Vascular process In majority of patients, the etiology is proposed but not found
Classification of Seizures• Traditionally divided into “ grand mal” and “petit mal” seizures• ILAE classification of epileptic seizures in 1981 based on clinical observation and EEG findings• Seizures were divided into partial and generalized seizures based on loss of consciousness• Partial seizures were divided into simple partial and complex partial based on alteration of consciousness
Observe seizure type Generalized seizuresLoss of consciousness? Complex partial Partial seizures Altered consciousness? Simple partial
Partial seizures (focal or localized)• In partial seizures just one side of the brain is affected. Simple partial seizures may causejerking motions or hallucinations, but the person often remains aware of what is happening.• Simple Partial Seizure• No loss of awareness• With sensory, motor, autonomic, or psychic signs• Complex Partial Seizure• Impaired consciousness. (patient is conscious but unaware of what he’s doing)• Duration (typically 30 seconds to 3 minutes)• Partial Seizure with Secondary Generalization• Begins focally, with or without focal neurological symptoms• Variable symmetry, intensity, and duration of tonic (stiffening) and clonic (jerking) phases• Typical duration 1-3 minutes• Postictal confusion, and somnolence.
Absence seizures Brief staring spells (“petit mal”) withimpairment of awareness 3-20 seconds Sudden onset and sudden resolution Often provoked by hyperventilation Onset typically between 4 and 14 years of age. Often resolve by 18 years of age. Some children experience up to 100 absence seizures in a day
Myoclonic seizures Brief, shock-like muscle contractions Typically bilaterally synchronous Impairment of consciousness difficult to assess (seizures <1 second) May progress into clonic or tonic-clonic seizure May be associated with a progressive neurologic deterioration
Atonic seizures Sudden loss of postural muscle tone When severe often results in falls When milder produces head nods or jaw drops. Consciousness usually impaired Duration - usually seconds, rarely more than 1 minute
Tonic-Clonic Seizures Associated with loss of consciousness and post-ictal confusion/lethargy Duration 30-120 seconds Tonic phase Stiffening and fall Often associated with ictal cry Clonic Phase Rhythmic extremity jerking
Treatment of epilepsy First Line Approved Anti-Epileptic Drugs (AEDs) Second Line (intractable epilepsy) Epilepsy Surgery Vagus Nerve Stimulation Therapy Experimental Therapy AEDs Implanted Devices
Treatment: Medication Most common drugs for epilepsy are the group called (Anti-epileptics) or (Anti- convulsants).Most anti-epileptic agents act either by blockade of depolarisation channels (Na+ and Ca++) OREnhancing the activity of GABA (neurotransmission inhibition)
Tegretol (Carbamazepine)(CBZ) Carbamazepine was discovered by chemist Walter Schindler at J.R. Geigy AG (now part of Novartis) in Basel, Switzerland, in 1953. Schindler then synthesized the drug in 1960, before its anti-epileptic properties had been discovered. Carbamazepine was first marketed as a drug to treat trigeminal neuralgia (formerly known as tic douloureux) in 1962. It has been used as an anticonvulsant and antiepileptic in the UK since 1965, and has been approved in the U.S. since 1974. It was first used to control mania at 1971.
Indications It’s used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia. It is also used off-label for a variety of indications, including Attention-deficit hyperactivity disorder (ADHD), Schizophrenia, phantom limb syndrome, Complex regional pain syndrome, Paroxysmal extreme pain disorder, Neuromyotonia, intermittent explosive disorder, borderline personality disorder, post-traumatic stress disorder.
PharmacokineticsBioavailability 80 % (CR tab is less by 15% than other forms)Protein binding 76 % Hepatic by CYP3A4 to active epoxideMetabolism from (10,11 epoxide)Half-life (25-65) hours 72 % in urine (2-3) % unchangedExcretion 28 % in fecesTherapeutic range (17-50) ngm/mlSaliva conc. (20-30) %(Compared with plasma conc.)Breast milk conc. (25-60) %(Compared with plasma conc.)Placental barriers Cross Syrup 2 hours PPCReached Conv. tab 12 hours after CR tab 24 hours (CR is less by 25% than conv. tabs). Single dose 36 hours T1/2 Multiple doses 16-24 hours
Tegretol precautionsDo not start taking Tegretol without tellingyour doctor if you are pregnant or planningto become pregnant. Seizure control is veryimportant during pregnancy. The benefit ofpreventing seizures may outweigh any risksposed by taking Tegretol, do not stop takingit without your doctors adviceDO NOT take Tegretol if you have:• a history of boneif you are allergic to carbamazepine or an antidepressant such as imipramine marrow suppression• (Tofranil).
Tegretol in Novartis sales (2007) Sales Name Indication(s) (US$millions) Diovan Hypertension 5000 Gleevec Chronic myelogenous leukemia 3100 Zometa Cancer complications 1300 Sandostatin Acromegaly 1000 Sandimmune and Neoral Organ transplantation 944 Femara Breast cancer 937 Trileptal Lotrel Hypertension 748 Voltaren Trileptal anti-inflammatory Epilepsy 747 692 9th Lescol hypercholesterolemia 665 Exelon Alzheimers disease 632 Comtan Parkinsons disease 420 Tegretol Epilepsy 413 Lucentis Age-related macular 393 Tegretol degeneration Ritalin Exjade AD/HD Iron chelator 375 357 13th Tobramycin Cystic fibrosis 273
Mechanism of action The mechanism of action of carbamazepine and its derivatives is relatively well understood. Carbamazepine stabilizes the inactivated state of Voltage-gated sodium channels, making fewer of these channels available to subsequently open. This leaves the affected cells less excitable until the drug dissociates. Carbamazepine has also been shown to potentiate GABA receptors made up of alpha1, beta2, gamma2 subunits
• Kwan and Brodie. NEJM 2000; 342: 314-319.• Mohanraj and Brodie. Epil Behav 2005; 6: 382-387
Tegretol provides excellent sensory symptomes relief in diabetic neuropathy patientsPatients with diabeticneuropathy after sixweeks of treatment ofCBZ with daily dose of600mg.An update on the pharmacologicalmanagement of post-herpeticneuralgia and painful diabeticneuropathy . CNS drugs.2008;22(5) :417-42
Carbamazepine and phenytoin. Comparison ofcognitive side-effects in epileptic patientsduring monotherapy and withdrawal. We compared the cognitive effects of carbamazepine and phenytoin with neuropsychological tests exploring intelligence, vigilance, attention, memory, and visuomotor performances in 25 epileptics (13 receiving carbamazepine and 12 receiving phenytoin) and 26 matched normal controls. Patients were seizure free for at least two years and taking prolonged monotherapy. We also evaluated the effects of drug withdrawal by retesting patients three months after reduction at half drug dose and three months and one year after complete withdrawal. Our findings suggest that phenytoin affects the cognitive functions more than carbamazepine does, although the negative effects of both drugs are reversible by complete therapy withdrawal. Arch Neurol. 1988 Aug;45(8):892-4. http://www.ncbi.nlm.nih.gov/pubmed/3395263