VII. SIDE EFFECTS AND DRUG INTERACTIONSLamotrigine*Status EpilepticusHISTORY Ancient Times: “Seizure” may have originated from belief that epileptics were “seized by the devil.” “Epilepsy” is derived from the Greek “epilambanein” meaning “to seize or attack.”1850 : Bromides discovered 1870: John Hughlings Jackson proposed first rational mechanism for seizures.1912: First clinical use of phenobarbital to treat epilepsy1929 - 1938: Hans Berger developed the EEG and showed the relationship between discharges in the brain and the clinical manifestations of epileptic seizures. 1938: Merritt and Putnam systematically studied 746 compounds and discovered phenytoin as effective antiseizure drug. DEFINITIONS: Seizures: result from abnormal neuronal discharge in the central nervous system produced by either focal or generalized disturbances of brain tissue. They result in abnormal phenomena of motor (convulsion), sensory, autonomic, or psychic origin.Epilepsy: A condition characterized by recurrent seizures of a particular pattern unprovoked by any immediate identified cause. Incidence = 1/300 to 1/100 Epileptic Syndromes: A cluster of symptoms frequently occurring together, including seizure types, precipitating factors, age of onset, family history, prognosis, etc.. ETIOLOGY AND MECHANISMS:Epileptic seizures are result from hyperexcitable neurons caused by:1. Increased activity of voltage-gated ion channels (e.g., Na+ & Ca++ channels)2. Decreased inhibitory (i.e., GABA) neurotransmission3. Increased excitatory neurotransmission (i.e., glutamate receptors)4. Alteration of extracellular ion concentration (e.g., potassium, calcium).ANTISEIZURE DRUGSDental PharmacologyRandal A. Skidgel, Ph.D.Dept. of Pharmacology1Classification of SeizuresSeizure Type FrequencyLoss ofConsciousness Duration FeaturesPARTIAL (FOCAL)Simple partial 10 % No 20 - 60 sec Focal motor (specific muscle groups), sensory (e.g., tingling, hot or cold sensations) or speech disturbancesComplex partial 35 % Impaired 30 sec to2 minComplex symptoms; confused behavior, dreamy state, amnesia; often associated with automatisms (purposeless movements).Partial with secondarily generalized tonic-clonic seizure10 % Yes 1 - 2 min Simple or complex partial seizure evolves into loss of consciousness, rigid extension of trunk and limbs (tonic), then rhythmic contraction of arms and legs (clonic).GENERALIZEDTonic-Clonic(grand mal)30 % Yes 1 - 5 min Loss of consciousness; massive contraction of skeletal muscle; rigid extension of trunk and limbs (tonic; posture called opisthotonos), then rhythmic contraction of arms and legs (clonic). Absence (petit mal) 10 % Impaired < 30 sec Abrupt brief onset of impaired consciousness, cessation of activities and staring. Characteristic 3 per second spike and wavepattern on EEG. Commonly in children (3 - 15 years old).Myoclonic < 3 % No 1 - 5 sec Brief, shocklike contraction of muscles; may be restricted to part of extremity or may be generalized. Can occur in clusters for several min.Atonic/Akinetic < 2 % Yes 5 sec - mins Sudden loss of postural tone leading to sagging of the head or falling. Sudden freezing of motion (called “akinetic”)2Status Epilepticus 7% Yes >5 min A state of continuous seizure activity of > 5 min or 2 or more discrete seizures between which baseline consciousness is not regained. This is a medical emergency that can be fatal up to 35% of the time.3Figure 1. Pathways of seizure spread. A, Focal seizure with spread to adjacent and contralateral cortical regions. B,Focal seizure with secondary generalization. Seizure discharge activates subcortical centers (A), which then activate entirecortex (B). C, Primary generalized absence seizure in which thalamocortical relays are believed to act on a diffuselyhyperexcitable cortex.Figure 2. Relationship between cortical EEG, extracellular and intracellular recordings in a seizure focus. A, Seizurewas induced by local application of a convulsant agent. The extracellular recording was made through a high-pass filter.Note the high-frequency firing of the neuron evident in both extracellular and intracellular recording during the paroxysmaldepolarization shift (PDS). This seizure is representative of a partial with secondarily generalized tonic-clonic seizure. B,Recording during an absence seizure, demonstrating the characteristic generalized spike and wave discharges at afrequency of 3 per second.4DRUG THERAPY OF EPILEPSY AND SEIZURESMechanisms of action of antiseizure drugs:Major known mechanisms by which antiseizure drugs work: 1. Prolongs Inactivation state of voltage-dependent Na+ channels in a use-dependent fashion.2. Increase the effectiveness of inhibitory GABA transmission via the GABAA receptor.3. Inhibition of Ca++ currents through T-type Ca++ channels.4. Inhibition of excitatory glutamate transmission via ionotropic receptors.Figure 3. Prolongation of Na+ channel inactivation state by antiseizure drugs. A, resting state in which Na+ channel activation gate (A) is closed. B, Arrival of an action potential causes depolarization and opening of activation gate (A) and Na+ flows into the cell. C, As depolarization continues, an inactivation gate (B) moves into the channel. Some antiseizure drugs (black box; e.g., phenytoin) prolong the inactivated state of the channel, presumably by preventing reopening of the inactivation gate. 5Figure 4. Enhancement of GABA transmission by antiseizure drugs. In the presence of the transmitter GABA, theGABAA receptor opens, allowing an influx of Cl-, which in turn, increases membrane polarization (hyperpolarizes), reducingthe likelihood of firing of the neuron. Some antiseizure drugs (top) work by reducing the metabolism of GABA. Others act atthe GABAA receptor, enhancing Cl- influx in response to GABA.Figure 5. Reduction of current through T-type Ca++ channels by antiseizure drugs. Some drugs reduce the flow of Ca++through T-type Ca++ channels, thus reducing pacemaker current that underlies the thalamic rhythm in spikes and waves seenin generalized absence seizures.6Figure 6. Effect of Antiseizure Drugs on Glutamate Receptors. Antiseizure drugs that reduce sodium channeltransmission will indirectly affect glutamate transmission by decreasing the amount of transmitter released from thepresynaptic terminal. Felbamate and