Antiseizure Pharmacology PDF

School of Medicine ANTIZEISURE PHARMACOLOGY Dr. Gabriel Gerardo N. Cortez November 14, 2024 OUTLINE SEIZURE...........................................................................................................1 SEIZURE EPILEPSY.....................................................................................................1 - Sudden change in behavior caused by electrical hyper SEIZURE MECHANISM...............................................................................1 synchronization of neuronal networks in the cerebral cortex. FIRST STEP: SHORT IN THE CIRCUIT............................................. 2 - Abnormal, excessive neuronal activity in the brain leading to SECOND STEP: DRIVING OF OTHER NORMAL NEIGHBORS....... 2 various clinical symptoms THIRD STEP: FAILURE OF INHIBITION.......................................... 3 ILAE 2017 CLASSIFICATION OF SEIZURE TYPES...................................... 3 FOCAL ONSET................................................................................... 3 EPILEPSY GENERALIZED ONSET...................................................................... 3 - At least 2 unprovoked seizures occurring more than 24 hours UNKNOWN ONSET........................................................................... 3 apart. UNCLASSIFIED.................................................................................. 3 - 1 unprovoked seizure and probability of further seizures FOCAL TO BILATERAL TONIC-CLONIC........................................... 3 similar to the general recurrence risk after two unprovoked HISTORY OF ANTI-EPILEPTIC DRUGS....................................................... 4 seizures occurring over the next 10 years. ANTI-SEIZURE MEDICATION CLASSIFICATION........................................ 4 o Unprovoked seizures mean there is no underlying FOCAL SEIZURE AEDS................................................................................... 4 cause. CARBAMAZEPINE...................................................................................... 4  In post-stroke seizures, since the brain OXCARBAZEPINE....................................................................................... 5 has been damaged already (because of LACOSAMIDE............................................................................................. 5 scarring cause in the brain – permanent PHENYTOIN................................................................................................ 5 brain damage) there is a high FOSPHENYTOIN......................................................................................... 6 probability that seizures will occur in GABAPENTIN...............................................................................................7 the future. PREGABALIN...............................................................................................7 Still considered as epilepsy. TIAGABINE.................................................................................................. 8 o As contrast with Acute Symptomatic and Acute RETIGABINE (EZOGABINE)....................................................................... 8 Non-Symptomatic Seizures which occurs due to FOCAL SEIZURE & CERTAIN GENERALIZED ONSET SEIZURES AEDS... 8 underlying cause such as stroke, hemorrhage, LAMOTRIGINE............................................................................................ 8 infection, metabolic problem etc. LEVETIRACETAM........................................................................................ 8  Once underlying cause is treated, PERAMPANEL............................................................................................. 9 seizures will resolve. PHENOBARBITAL...................................................................................... 9 - Diagnosis of an epilepsy syndrome. FELBAMATE................................................................................................ 9 o Not all seizures are the same. Some seizures are GENERALIZED ONSET AEDS...................................................................... 10 because of genetic mutations (e.g., Lennox- VALPROATE (VALPROIC ACID/DIVALPROEX).................................... 10 Gastaut, Dravet’s Syndrome). TOPIRAMATE............................................................................................ 10 ZONISAMIDE............................................................................................ 10 SEIZURE MECHANISM ABSENCE SEIZURE AEDS:............................................................................11 ETHOSUXIMIDE........................................................................................11 LENNOX-GASTAUT SYNDROME AEDS:.....................................................11 CLOBAZAM................................................................................................11 RUFINAMIDE..............................................................................................11 DRAVENT SYNDROME................................................................................ 12 CANNABIDIOL.......................................................................................... 12 INFANTILE SPASM / WEST SYNDROME.................................................. 12 VIGABATRIN............................................................................................. 12 TUBEROUS SCLEROSIS AEDS................................................................... 12 EVEROLIMUS............................................................................................ 12 OTHER AEDS FOR SEIZURES AND EPILEPSY......................................... 13 - Three things will have to occur for a person to have epilepsy. DIAZEPAM................................................................................................. 13 o (1) Paroxysmal Depolarization Shift: In simpler MIDAZOLAM............................................................................................. 13 terms, a short in the circuit of the brain. LORAZEPAM............................................................................................. 13 o (2) Neuronal Synchronization: Driving of other CLONAZEPAM.......................................................................................... 14 normal neighbors. CARBONIC ANHYDRASE INHIBITORS...................................................... 14 o (3) Transition to Ictus: Failure of Inhibition of ACETAZOLAMIDE..................................................................................... 14 neuronal action potential STATUS EPILEPTICUS................................................................................. 14  Ictus: Onset of seizures due to spread of EARLY STATUS EPILEPTICUS................................................................ 14 electrical impulse. ESTABLISHED STATUS EPILEPTICUS.................................................. 15  Will cause seizure REFRACTORY STATUS EPILEPTICUS................................................... 15  Paroxysmal depolarization is not SUPER REFRACTORY STATUS EPILEPTICUS...................................... 15 enough to cause seizure, the failure of AEDS AND CONTRACEPTION................................................................ 15 inhibition of neuronal ANTI-EPILEPTIC DRUGS CAUSING CONTRACEPTIVE FAILURE. 15 synchronization/action potential will ANTI-EPILEPTIC DRUGS CAUSING CONTRACEPTIVE FAILURE determine the presence of seizure. AT HIGH DOSES............................................................................. 15 ANTI-EPILEPTIC DRUGS WITH NO KNOWN EFFECT ON CONTRACEPTIVE FAILURE............................................................ 15 Note: Failure of Inhibition of Neuronal Synchronization / Action Potential AEDS AND TERATOGENICITY.................................................................... 16 - Main problem in seizure. SUMMARY TABLE........................................................................................ 16 REFERENCES................................................................................................. 17 Abad | Bulaon | Fabros | Jacob | Manalili, J. | Manalili, N. | Mendoza | 1 Quia Antiseizure Pharmacology SECOND STEP: DRIVING OF OTHER NORMAL NEIGHBORS - (1) Na+ Channels Open: The cell becomes more negative (approximately –70 mV). Na+ enters becomes more positive causing the membrane potential to rise towards the threshold of excitation. This initial inﬂux of Na+ contributes to the depolarization phase, which leads to the activation of FIRST STEP: SHORT IN THE CIRCUIT neuron. Once it reached -55 mV, irreversible depolarization - Seizures come from neurons, from cell bodies of grey matter occurs. where seizures arise. - (2) K+ channels Open: K+ ions begin to leave the cell, leading - Critical in the occurrence of seizures include other areas of to repolarization bringing the membrane potential to a more the brain speciﬁcally the astrocytes. negative state. Bringing back membrane potential toward its - Astrocytes becomes excited as well and binds up the resting state glutamate released by neurons and sometimes would - (2) Na+ Channels Close: as the membrane potential peaks. release glutamate of their own. - (2) K+ leaves the cell: causing hyperpolarization, a more - This would cause an excess in Glutamate or decrease in negative stage below the resting state. GABA inhibition. - (3) K+ Channels close: Causing a refractory period wherein o Astrocytes: Surrounds all neurons any stimulation will not cause action potential. o Glutamate: Excitatory neurotransmitter - Excess K+ outside diffuses away returning to resting membrane potential. - This ﬁgure shows the end of a Paroxysmal Shift in Depolarization (1st step in seizure). - Epilepsy - Seen in EEG are spike and slow-wave. o There is repeated paroxysmal depolarization in a large enough group of neurons that elevate the extracellular K+ concentration. - This increase in extracellular K+ can make neighboring neurons more excitable, amplifying the seizure activity and spreading it through neural circuits. - A single neuron, representing a single-unit recording of an action potential during a seizure. - Being stimulated multiple times, increasing excitability. Abad | Bulaon | Fabros | Jacob | Manalili, J. | Manalili, N. | Mendoza | 2 Quia Antiseizure Pharmacology o Diagnosis: Focal Onset, Aware, Motor Onset Tonic- Clonic seizure. - Motor Onset o Automatism – examples are lip smacking or blinking are also actual seizures. o Atonic – “drop attacks” or the body suddenly loses tone and patient suddenly falls. o Clonic – “jerking” o Epileptic Spasm – usual in cases of Lennox- Gastaut Syndrome or West syndrome in infantile cases. o Hyperkinetic – “movement disorders” that - Increased extracellular K⁺ concentration prevents K⁺ from appears like basal ganglia problems but are actual diffusing out effectively, leading to a "partial depolarization" seizures. state where neurons become more easily excitable. o Myoclonic – just like Epileptic Spasm but in adults, elderly, or post-arrest patients. o Tonic – “stiffening” - Non-Motor Onset o Autonomic – lacrimation (sympathetic / parasympathetic problems) o Behavior Arrest – blank stares o Cognitive – memory lapses o Emotional – depression (rare type of seizures) o Sensory – numbness, visual problems GENERALIZED ONSET - No classiﬁcation for Aware or Impaired Awareness because - The accumulated extracellular K⁺ can lead to depolarization if you affect the general part or the whole brain, the patient of surrounding neurons, increasing the likelihood of should not be awake. If generalized onset, the patient synchronized ﬁring, which is a hallmark of seizure activity. should not be aware always. o This is one way to diagnose if patient is having THIRD STEP: FAILURE OF INHIBITION Focal or Generalized Onset seizure. - (1) Loss of After-hyperpolarization o If patient is having generalized seizure but is o Will have no overshoot awake, is it truly a seizure? No. o Increased ability to stimulate/excite neurons  Patient may be having psychogenic or - (2) Loss of the surround inhibition (GABA Inhibition) functional seizures (anxiety). - (3) Excess glutamate stimulation - Motor - (4) Increase in intracellular from calcium (From glutamate) - Non-Motor (Absence) - (5) Recurrent excitatory feedback circuit o Typical - Will eventually leads to seizures o Atypical o Myoclonic o Eyelid Myoclonia Note: - All previously discussed are just a review of neuro-physiology. Note: Doc mentioned he will not ask questions in that part. Only way to differentiate Typical and Atypical Absence Seizure - EEG Findings ILAE 2017 CLASSIFICATION OF SEIZURE TYPES UNKNOWN ONSET - When no one saw how the patient had seizures. - There is tongue biting, incontinence, patient is already jerking and generalized but not sure if it started as focal or generalized. - Motor o Tonic-clonic o Epileptic Spasms - Non-Motor o Behavior Arrest UNCLASSIFIED - Can no longer be categorized. FOCAL TO BILATERAL TONIC-CLONIC - Seizures classiﬁed before as Focal Seizures with secondary Generalization. FOCAL ONSET - Started from one side and eventually generalizes because - Starts on one side of the body (either left or right or just arm the neuronal synchronization spreads to the other side of or just the leg). the brain. - May be Aware or Impaired Awareness (formerly known as Simple and Complex). - Aware – means patient is conscious. - Impaired Awareness – not conscious. o For example: Patient has tonic-clonic seizures of the right arm but he is awake. Abad | Bulaon | Fabros | Jacob | Manalili, J. | Manalili, N. | Mendoza | 3 Quia Antiseizure Pharmacology HISTORY OF ANTI-EPILEPTIC DRUGS - GABA Transaminase: Vigabatrin - Cl- Channels: Benzodiazepine FOCAL SEIZURE AEDS - Phenobarbital (1913) – ﬁrst medication that was introduced. - Other ﬁrst generations CARBAMAZEPINE o Phenytoin o Acetazolamide Seizure Type Focal or Generalized Tonic Seizures - Brivaracetam – latest in the market MOA - Na+ Channel inhibitor - Everolimus – not a seizure medication, but an oncologic - 15-20 mg/kg/d (children) medication but sometimes used in speciﬁc seizure Dosage - 800-1200 mg/d (adult) syndrome. - 1600 mg/d (max recommended dose) - A: variable, may take a few days to ANTI-SEIZURE MEDICATION CLASSIFICATION reach therapeutic levels - Sodium Channel Blockers - M: Liver (CYP34A4), with renal excretion Kinetics - Calcium Channel Blockers of metabolites - GABA Enhancers - T ½: 25-65 Hours (decrease over time - Glutamate Inhibitors due to autoinduction) - Others (SV2A Binding Drugs, Carbonic Anhydrase Inhibitors) - GI discomfort, dizziness, blurred vision, diplopia or ataxia, sedation at high doses, weight gain Side Effects - Benign leukopenia - Rash – Stevens-Johnson Syndrome (HLA-B*1502 allele) – common in Asians - Potent inducer of CYP3A4 - Valproate – may inhibit CBZ clearance ~ Drug increase steady-state CBZ blood levels Interactions - Phenytoin and Phenobarbital – decrease steady state concentrations - Autoinduction – reduced in plasma concentration after the 1st 2 months of use - May exacerbate myoclonic or absence seizures Other - First choice for Trigeminal Neuralgia - Mood stabilizer (bipolar disorder) - Epoxide metabolite (toxicity) - Na+ Channels: Phenytoin, Carbamazepine, Lamotrigine, - Monitoring: CBC, liver function tests, Lacosamide, Zonisamide, Oxcarbazepine serum levels; genetic testing for HLA- - K+ Channel and post-synaptic K+ Channel: B*1502 - Retigabine - Alpha-2-Delta Receptor: Gabapentin, Pregabalin - Used mainly for Focal but used sometimes as Adjunct for - NMDA Receptors: Felbamate Generalized Seizures. - AMPA Receptors: Perampanel - Autoinduction o Drug increases its own metabolism overtime. o For example, you prescribe Carbamazepine 200 mg 3x a day. After 3 to 4 weeks, the drug will not be effective anymore because it induces its own metabolism. You have to increase the dosage already. - Trigeminal Neuralgia o First drug of choice is Carbamazepine. o It is not a seizure activity; it is a problem in trigeminal nerve where in there will be pain on the distributions of your trigeminal nerve usually on one side of the face. Abad | Bulaon | Fabros | Jacob | Manalili, J. | Manalili, N. | Mendoza | 4 Quia Antiseizure Pharmacology - Can be used as a mood stabilizer for patients with Bipolar- o Cause Acute Symptomatic Seizure because of Disorder. Hyponatremia. - The epoxide metabolite toxicity will be increased by o If this happens, you need to change the valproate and this cause the SJS. medication. - What will you monitor in Carbamazepine? - No Autoinduction o CBC o You don’t have to increase dosage usually after a o Liver Function Test – because it is metabolized by few weeks or months after giving the medication, the liver because the metabolism will still stay the same. o Serum Levels o Carbamazepine Assays – rarely done nowadays o Genetic testing for HLA-B*1502 (if available) Note: Important to remember in Carbamazepine  If present do not give carbamazepine - SJS anymore because risk of developing SJS - Autoinduction is high. - Epoxide metabolite Important to remember in Oxcarbazepine STEVENS-JOHNSON SYNDROME - Hyponatremia - No autoinduction - Patients under Carbamazepine who shows signs of small - 10-monohydroxyl metabolite rashes are advised to return for consultation and discontinue the medication right away because presence of even small rashes could lead to SJS. LACOSAMIDE o Caused by: epoxide metabolite toxicity Seizure Type Focal or Generalized Tonic-Clonic Seizures MOA - Na channel inhibitor - 200 mg/d ~ 400 mg and 600 mg/d - Higher dose may provide better control of focal bilateral tonic-clonic Dosage seizure - 50 mg BID ~ increasing by 100mg increments weekly - A: rapid and complete absorption in adults; nearly 100% bioavailability; - Example of a benign SJS. Kinetics peak 1-4 hours (oral dosing); - Some cases will have excoriations of the skin. - M: liver (CYP2C19) - T ½: 13 hours OXCARBAZEPINE - Dizziness, headache, nausea, diplopia Side Effects - Cardiac arrhythmias (PR prolongation) Seizure Type Focal or Generalized Tonic-Clonic Seizures Drug - Does not induce or inhibit cytochrome MOA - Na channel inhibitor Interactions P450 isoenzymes – minimal interactions Dosage - 300-600 mg/d ~ 900 - 2400mg/d - Oral – contains aspartame (source of - A: rapid and almost completely phenylalanine) – harmful in patients absorbed (>95%); peak levels 6-8 hours Other with phenylketonuria after administration - Baseline and periodic ECG (esp. in Kinetics - M: liver, with renal excretion of patients with cardiac condition) metabolites - T ½: 9 hours - Sometimes used also as adjunct for generalized tonic-clonic - GI discomfort, dizziness, blurred vision, seizures. diplopia or ataxia, sedation at high - Avoid giving this to patients who are elderly who have doses, weight gain cardiac problems, or even young with cardiac problems. Side Effects - benign leukopenia o Causes PR prolongation especially if there are - Rash ~Steven-Johnson syndrome (GLA- other medications on the list of patients that are B*1502 allele) – common in Asians prone to cause PR prolongation. - Hyponatremia - Potential to reduce the effectiveness of Note: Drug hormonal contraceptives Lacosamide “LOVE” Interactions - Less hepatic enzymes vs CBZ - Lovecosamide = heart = Cardiac Arrhythmias (minimized drug interactions) - No autoinduction PHENYTOIN - Less potent that CBZ~may need to be 50% higher than those of CBZ to obtain equivalent seizure control Focal Or Generalized Tonic-Clonic Seizures Other Seizure Type - 10-monohydroxyl metabolite (less Acute Treatment of Status Epilepticus (IV Form) toxic vs epoxide from CBZ) MOA - Na channel inhibitor - Monitoring: Serum Sodium; Liver - Loading dose (oral or IV): 15-20 mg/kg Function and Renal Function - Maintenance: 300-400 mg/day in divided doses (adjust based on Dosage - Less chances of SJS because it will have a different therapeutic levels metabolite (10-monohydroxyl metabolite) which is less toxic - Therapeutic plasma level: 10-20 than the epoxide metabolite of carbamazepine mcg/ml (total) - Hyponatremia - A: variable; highly dependent on the o Normal serum sodium is 135-145 mEq/L formulation; peak of extended-release o Some patients who loss to follow up, come back Kinetics capsule ~ 4-12 hours; with further seizures due to hyponatremia. - Non-extended release: 1.5 to 3 hours; highly protein-bound Abad | Bulaon | Fabros | Jacob | Manalili, J. | Manalili, N. | Mendoza | 5 Quia Antiseizure Pharmacology - M: liver (CYP2C9, CYP2C19); at low blood - Most antiseizure medications will exhibit First Order Kinetics levels – First Order Kinetics or a linear kinetics, as you increase the dose you increase - At higher doses – Zero Order Kinetics average serum concentration of your patient. (non-linear) - The fraction per unit time of the drug is eliminated, however - T ½: 12-336 hours (average of 24 hours) in phenytoin as the dose increases there will be saturation ~ can vary due to dose-dependent of the metabolism. kinetics o This causes toxicity. - Nystagmus and loss of smooth o Conduct Phenytoin Assay to monitor if it is in the extraocular pursuit movements therapeutic level of 10-20 mcg/ml. - Diplopia and ataxia – Most common dose related adverse effects requiring PURPLE GLOVE SYNDROME dose adjustments - Sedation, dizziness - Gingival hyperplasia and hirsutism; coarse facial features Side Effects - Long term: osteopenia (increased vitamin D metabolism), peripheral neuropathy - Purple glove syndrome (IV administration); low plasma albumin ~ toxicity - Toxicity signs: CNS depression, nystagmus, ataxia, confusion, seizures. - Strong inducer of CYP3A4; interacts with many drugs including warfarin, oral Drug contraceptives Interactions - Valproate inhibits phenytoin metabolism ~ toxicity - Oldest nonsedating AED used in the treatment of epilepsy - No longer considered a first-line chronic therapy – A/E and drug to drug interactions GINGIVAL HYPERPLASIA - May worsen idiopathic generalized Other epilepsies; absence and JME; Dravet syndrome - Cannot be given intramuscularly - Monitoring: therapeutic levels; CBC, liver function tests, bone density testing - 10-20 mcg/ml = therapeutic dose o Dose above this may cause toxicity o Dose below this will not improve seizure control - First order kinetics o Linear type = as you add the dose there will be expected metabolism expected excretion of the drug - Phenytoin is prominent in causing nystagmus and loss of smooth extraocular pursuit movements. - In patients with low plasma albumin – may develop toxicity. - Do not combine Phenytoin and Valproate. - Need conduct cardiac monitoring as it may also cause hypotension and cardiac arrythmias. FOSPHENYTOIN ZERO ORDER KINETICS Acute Treatment of Status Epilepticus Short Seizure Type Term Substitute for Oral Phenytoin When Oral Administration is not Possible MOA - Na channel inhibitor - Loading dose: 15-20 mg PE (phenytoin equivalents) // kg IV or IM Dosage - Maintenance: individualized based on phenytoin levels and clinical response - A: rapidly converts to phenytoin after IV or IM administration - M: liver (CYP2C9, CYP2C19), similar to Kinetics phenytoin - T ½: 15 minutes for Fosphenytoin converts quickly to phenytoin with its ~ 24-hour half-life - Dizziness, drowsiness, nystagmus, Side Effects ataxia Abad | Bulaon | Fabros | Jacob | Manalili, J. | Manalili, N. | Mendoza | 6 Quia Antiseizure Pharmacology - Hypotension, bradychardia (esp. with rapid IV administration) - Lower risk of phlebitis and tissue damage compared to phenytoin Drug - Similar to phenytoin, as it converts to Interactions phenytoin in the body - Blood pressure and cardiac monitoring during and after IV infusion (risk of hypotension and arrythmias) - Therapeutic drug monitoring for Other phenytoin levels (10-20 mcg/ml target) - Liver function tests and CBC monitoring - Can be given intramuscularly - No purple glove syndrome develops - Not used as phenytoin replacement maintenance. GABAPENTIN Seizure Focal Seizures (Adjunct Therapy) Types - Binds to the α2δ subunit of voltage- - Zero-Order Kinetics of Gabapentin is the opposite of gated calcium channels, reducing phenytoin. MOA excitatory neurotransmitter release - Orally administered Gabapentin also exhibit zero-order o Block calcium release → No kinetics, but in contrast with orally phenytoin becomes excitation saturated because of absorption. - Start low and titrate up (e.g., 300 mg once daily, increasing to 300 mg three times daily) PREGABALIN Dosage - Maximum dose for seizures and neuropathic pain: 1800-3600 mg/day in Seizure Focal Seizures (Adjunct Therapy) divided doses Types - A: Saturable at high doses, requires - Binds to the α2δ subunit of voltage- divided dosing MOA gated calcium channels, reducing Kinetics - M: Not metabolized; Excreted excitatory neurotransmitter release unchanged in urine - Seizures: typically 150-600 mg/day in - T ½: 5-7 hours divided doses; 50-75mg/day (may avoid - Somnolence, Dizziness, Ataxia, side effects during initiation) Dosage Side Effects Headache, Tremor - Neuropathic pain/fibromyalgia: Start 75 - Weight gain, Peripheral edema mg twice daily, titrate up to 300-600 - Minimal (no significant CYP450 mg/day in divided doses Drug interactions) - A: Rapidly absorbed, with high Interactions - Antacids may decrease gabapentin bioavailability (~90%) absorption; separate by at least 2 hours. Kinetics - M: Not metabolized - Used for neuropathic pain (diabetic o Excreted unchanged in urine neuropathy, postherpetic neuralgia); - T ½: 6 Hours restless leg syndrome; anxiety disorders - Somnolence, Dizziness, Ataxia, (off-label use) Side Effects Headache, Tremor Others - May aggravate absence and myoclonic - Weight gain, Peripheral edema seizures - Minimal (no significant cyp450 - Caution in renal impairment interactions) Drug - Monitoring: Renal function - Antacids may decrease gabapentin Interactions absorption - Given for Focal Seizures only as Adjunct Therapy and not o Separate by at least 2 hours. given as the ﬁrst-line. - Used for neuropathic pain (diabetic - Side Effects neuropathy, postherpetic neuralgia) o Prescribe with informing to patient the usual SE of o Restless leg syndrome drowsiness or sleepiness which persist up to 1-5 o Anxiety disorders days, but after that the patient will become Others - May aggravate absence and myoclonic tolerated to the SE seizures o If the patient did not tolerate, decrease the dose, - Caution in renal impairment or use an alternative - Monitoring: Renal function - Caution in renal impairments: o Patient with CKD will need to go dose adjustments. Note: Gabapentin and Pregabalin - Gabapentinoids - Almost same mechanisms and interaction - Binds to the α2δ subunit of voltage-gated calcium channels Abad | Bulaon | Fabros | Jacob | Manalili, J. | Manalili, N. | Mendoza | 7 Quia Antiseizure Pharmacology TIAGABINE Seizure Types Focal Seizures (Adjunct Therapy) - GABA reuptake inhibitor ~ blocking MOA GABA transporter (GAT-1), increasing GABA availability - Start low and titrate up to avoid CNS side effects; Initial dose: 4 mg/day Dosage - Typical maintenance dose: 16-56 mg/day, divided 2-4 times daily - A: Rapidly absorbed, peak levels in ~45 minutes Kinetics - M: Primarily Hepatic (CYP3A4 Pathway) - T ½: 5-9 Hours - Dizziness, drowsiness, confusion, - Discoloration of the lips, eyelids, nails, and tongue and Side Effects ataxia, tremor sometimes will cause vision abnormalities. - Metabolized by CYP3A4 Drug - Interacts with inducers and inhibitors Interactions Review: of this enzyme Drugs for Focal Seizures (Sodium Channel Inhibitors) - Monitor liver function tests - Carbamazepine Others - May worsen in Generalized Onset - Oxcarbazepine Seizures (contraindicated) - Phenytoin - Fosphenytoin - Not available in the Philippines. - Lacosamide - If GABA inhibitors did not reuptake in the synapse → GABA Drugs for Focal Seizures (α2δ subunit) will accumulate along the synapse → Inhibition of the action - Gabapentin - Pregabalin potential Drugs for Focal Seizures (GABA Reuptake Inhibitor – GAT-1) - Tiagabine Note: Drugs for Focal Seizures (Potassium Channel – KCNQ2/3 Kv7) - TiaGABine = GABA reupTake inhibitor - Retigabine - Specifically blocks the GAT-1 receptor FOCAL SEIZURE & CERTAIN GENERALIZED ONSET SEIZURES AEDS RETIGABINE (EZOGABINE) LAMOTRIGINE Seizure Focal Seizures (Adjunct Therapy) Types Seizure Focal or Generalized Tonic-Clonic Seizures - Activates KCNQ2/3 (Kv7) Potassium Types Lennox-Gastaut Syndrome Absence Epilepsy MOA Channels, stabilizing resting membrane MOA - Na Channel Inhibitor potential and reducing excitability - Start low and titrate up gradually to - Initial dose: 100 mg three times daily minimize risk of rash Dosage - Maintenance: 200-400 mg three times - Initial dose varies based on concomitant daily Dosage medications; 25 mg/day if no enzyme - Absorption: Well-absorbed, peak levels inducers/inhibitors in ~0.5-2 hours - Typical maintenance: 100-400 mg/day in Kinetics - Metabolize: Primarily Hepatic divided doses (Glucuronidation, Acetylation) - A: Rapidly absorbed, high bioavailability - Half-Life: 6-10 Hours (~98%) - Blue discoloration of Lips, Skin, Retina - M: Primarily Hepatic (UGT Pathway); (risk of vision abnormalities) Kinetics Affected by enzyme inducers and Side Effects - Urinary retention, QT prolongation inhibitors - Drowsiness, Dizziness, Confusion, - T ½: 24-30 hours (reduced when co- Tremor administered with enzyme inducers) - Additive CNS depression with other - Stevens-Johnson Syndrome (Risk Drug sedatives increases with rapid dose escalation Side Effects Interactions - QT prolongation risk increases with - Aseptic Meningitis (rare complication) other QT-prolonging drugs - Dizziness, drowsiness, headache, nausea - Baseline and periodic eye exams (risk of - Levels decreased by enzyme inducers retinal abnormalities) Drug (e.g., carbamazepine, phenytoin) o During prescription of Interactions - Levels increased by enzyme inhibitors Others retigabine (e.g., valproic acid) - Monitor ECG - Bipolar disorder (maintenance therapy to - Assess for urinary retention symptoms Others prevent mood episodes) - Monitor: Rashes and Liver functions tests - Not available in the Philippines and in the market due to the side effects of blue discoloration lips, skin, and retina. - Lamotrigine and Lacosamide are both sodium channel - Lacosamide – another drug which causes QT prolongation or inhibitor (same “La”). cardiac arrythmia. - Lamotrigine and Carbamazepine – are prominent in causing SJS. LEVETIRACETAM Abad | Bulaon | Fabros | Jacob | Manalili, J. | Manalili, N. | Mendoza | 8 Quia Antiseizure Pharmacology Focal or Generalized Tonic-Clonic Seizures - Behavioral: aggression, irritability, Seizure Myoclonic Seizures in Juvenile Myoclonic anxiety, suicidal thoughts (risk of Types Epilepsy Side Effects serious psychiatric effects) - Binds to Synaptic Vesicle protein 2a - Dizziness, drowsiness, fatigue, (SV2a), modulating neurotransmitter headache MOA release and reducing neuronal - Induces and is metabolized by CYP3A4, - Hyperexcitability so interacts with strong CYP3A4 - Initial dose: 500 mg twice daily, titrate inducers (e.g., Carbamazepine, as needed Drug Oxcarbazepine, Phenytoin) = increases Dosage - Maintenance dose: 1000-3000 mg/day Interactions clearance by 50-70% ~ may require in divided doses higher dose. - A: Rapid and nearly complete - Enhanced CNS depression with other absorption with high bioavailability CNS depressants (>95%) - Monitor: liver function; mood and Kinetics Others - M: Minimally hepatic; primarily behavioral changes excreted unchanged by the kidneys - T ½ : 6-8 hours - With its drowsing effects, patients tend to have deep sleep. - Behavioral: irritability, agitation, mood changes (caution in patients with PHENOBARBITAL Side Effects history of mood disorders) - Drowsiness, dizziness, fatigue Seizure Focal or Generalized Seizures; Status - Minimal drug interactions; not Drug Types Epilepticus (In Refractory Cases) significantly metabolized by cyp450 Interactions - Enhances GABA-mediated chloride enzymes influx at GABA-a receptors, increasing - Monitor: renal function; mood and MOA Others inhibitory neurotransmission and behavioral changes depressing neuronal activity - Initial dose: 1-3 mg/kg once daily or in - Levetiracetam is the most commonly used anti-epileptic divided doses medication followed by Valproic Acid. - Maintenance dose: individualized based o If you are not sure on what type of anti-epileptic on serum drug levels and therapeutic you would give to the patient, give Levetiracetam. Dosage response o The protype that is broad spectrum of anti- - Therapeutic drug levels (goal: 15-40 epileptic content. mcg/ml) to minimize toxicity and o Still unknown mechanism in terms of seizure but optimize efficacy still very effective. - A: slow but complete, oral - In the US, they sometimes titrate this from 1000 mg up to bioavailability ~90% 4500 mg/day because people there are big (obese). Kinetics - M: primarily hepatic (CYP2C9 pathway); - If symptoms of psychiatric patients become worse, change - T ½: 53-118 hours in adults the drug into Valproic acid. - Dependence, tolerance, cognitive - Valproic acid – is the alternative to Levetiracetam, which is impairment also known for its mood stabilizing effects, therefore useful Side Effects - Drowsiness, dizziness, ataxia, sedation for psychiatric patient. - Respiratory depression, hypotension, - Dose adjustments are necessary for patients with CKD and hepatic toxicity undergoing dialysis. - Potent inducer of CYP450 enzymes; - IV form and oral form almost has the same bioavailability Drug interacts with many drugs, including that’s why for acute seizure, oral forms can also be given. Interactions warfarin, oral contraceptives - Therapeutic drug levels (goal: 15-40 Note: mcg/ml) to minimize toxicity and Levetiracetam Others optimize efficacy - Most commonly used drug - Liver function tests, especially in long- - Broad spectrum - Psychiatric side effects term use - SV2A - Monitor the kidney function (creatinine) - Oldest antiseizure and is still being used today. PERAMPANEL FELBAMATE Seizure Focal Seizures (12 Years Or Older) Or Seizure Focal Seizures or Lennox-Gastaut Syndrome (As Types Generalized Tonic-Clonic Seizures (Adjunct) Types Adjunctive Therapy) - Selective, non-competitive antagonist Multiple MOAs: MOA of AMPA receptors, reducing excitatory - Blocks NMDA receptors MOA neurotransmission - Modulates GABA-a receptors - Initial dose: 2 mg once daily, typically at - Inhibits sodium and calcium channels bedtime due to sedative effects - Initial dose: 1200 mg/day in divided Dosage - Titrate up slowly (max dose: 12 mg once doses (400mg TID) daily) based on response and Dosage - Maintenance dose: 2400-3600 mg/day in tolerability divided doses, titrated based on clinical - A: Rapid, peak plasma levels in 0.5-2.5 response hours - A: rapid and complete with high Kinetics bioavailability (~90%) - M: Primarily hepatic (CYP3A4 pathway); - T ½ : 105 hours Kinetics - M: primarily hepatic (CYP3A4, CYP2E1 pathways) - T ½: 20-23 hours Abad | Bulaon | Fabros | Jacob | Manalili, J. | Manalili, N. | Mendoza | 9 Quia Antiseizure Pharmacology - Aplastic anemia, acute hepatic failure Note: (limits its use) Valproic Acid Side Effects - Drowsiness, dizziness, headache, GI - V(all)proic acid - many mechanisms of actions upset o Same with Felbamate, but without NMDA actions - Inhibits and induces various CYP450 - For absence seizures, give Ethosuximide. However, it is not enzymes; can interact with phenytoin, available in the Philippines, so Valproic Acid is recommended. Drug - If the patient is female, either Levetiracetam or Valproic Acid can valproate, and carbamazepine Interactions be given. - Requires dose adjustments when combined with other anticonvulsants Others - Monitor: CBC; liver functions tests TOPIRAMATE Seizure Focal and Genralized Seizures; Lennox-Gastaut Review: Phenobarbital Types Syndrome (Adjunctive Therapy) - 15-40 mcg/ml Multiple MOAs: - GABA-A receptor - Blocks Voltage-gated sodium channels - Cognitive impairment - Enhances GABA Activity Levetiracetam MOA - Antagonizes AMPA/KAINATE Glutamate - SV2A receptors - Psychiatric side effects (limiting factor) - Inhibits Carbonic Anhydrase Perampanel - AMPA - Initial Dose: 25-50 mg/day, titrated up Felbamate slowly to reduce side effects - F(all)bamate = many mechanisms Dosage - Maintenance Dose: 100-400 mg/day in divided doses (seizures); 50-100 GENERALIZED ONSET AEDS mg/day (migraine prophylaxis) - A: Rapidly absorbed, unaffected by food VALPROATE (VALPROIC ACID/DIVALPROEX) - M: Partially metabolized in the liver; Kinetics 70% excreted unchanged in urine Seizure Focal And Generalized Seizures (Including - T ½: 21 hours (extended in renal Types Absence, Myoclonic and Tonic-Clonic) impairment) Multiple MOAs: - Cognitive: Confusion, memory - Increases GABA levels impairment, language difficulties MOA - Inhibits sodium channels (DOPAMAX EFFECT) - Modulates calcium channels Side Effects - Serious: Metabolic Acidosis, Kidney - Initial dose: 10-15 mg/kg/day, titrate up Stones, Glaucoma, Hyperthermia gradually - Dizziness, Drowsiness, Fatigue, Weight Dosage - Maintenance dose: typically, 500-3000 loss, Paresthesia mg/day, adjusted based on clinical - May decrease effectiveness of oral response and drug levels contraceptives - A: well-absorbed orally, food delays but Drug - Other carbonic anhydrase inhibitors does not reduce absorption Interactions may increase risk of metabolic acidosis - M: extensive hepatic metabolism and kidney stones Kinetics (primarily via UGT and beta-oxidation - Migraine Prophylaxis pathways) - Off Label: weight loss, bipolar disorder - T ½ : 9-16 hours (varies with age and and neuropathic pain liver function) Other - Monitor: Serum bicarbonate levels; - Hepatotoxicity, pancreatitis, renal function tests; cognitive side hyperammonemia, thrombocytopenia, effects and visual changes Side Effects teratogenicity - Nausea, vomiting, drowsiness, tremor, - DOPAMAX Effect is rarely encountered, as long as it is started weight gain slow (25-50mg). - Valproate inhibits metabolism of - Since it is a carbonic anhydrase inhibitor, it can cause Phenobarbital and Ethosuximide metabolic acidosis. - Valproate and Carbamazepine ~ CBZ - For female patients with migraine and seizure, topiramate Drug epoxide may be increased (increased can be given which can also cause weight loss, unlike in Interactions Carbamazepine toxicity: SJS) Valproate it can cause weight gain. However, it causes - Valproate decreases the clearance of cognitive impairment. Lamotrigine ~ 2-3-fold prolongation of Lamotrigine’s half-life - Bipolar disorder (mood stabilizer) Review: Drugs for Migraine prophylaxis - Migraine prophylaxis - Valproate - Drug of choice: for Juvenile Myoclonic - Topiramate Others Epilepsy - Monitor: CBC with Platelet count; liver function tests ZONISAMIDE - Always check the liver function (ALT, AST, Liver enzymes) due Focal Seizures (Adjunct Therapy); Generalized Seizure Types to hepatotoxicity. Seizures (Off-Label) - Monitor platelet count (do not give to patient with Multiple MOAs: Thrombocytopenia). - Blocks voltage-gated sodium channels MOA - Usually not given in young females due to its teratogenicity. - Blocks voltage-gated calcium channels - Reduce lamotrigine dose if given concomitantly with - Inhibits carbonic anhydrase Valproic Acid. - Initial Dose: 100 mg once daily, titrated Dosage up gradually Abad | Bulaon | Fabros | Jacob | Manalili, J. | Manalili, N. | Mendoza | 10 Quia Antiseizure Pharmacology - Maintenance Dose: 200-400 mg/day - Additive CNS depression with other CNS (often given in divided doses in adults) depressants - A: Well-absorbed orally Other - Monitor: CBC; Liver Function Tests; Rash - M: Primarily hepatic (CYP3A4 Pathway); Kinetics Some renal excretion LENNOX-GASTAUT SYNDROME AEDS: - T ½: 63 hours (Long half-life allows for - Epilepsy syndrome, severe rare form of epilepsy that once daily dosing) typically starts during childhood (2-6 years old), pediatric - Metabolic Acidosis, Kidney Stones, cases up to adulthood. Hyperthermia, Cognitive Impairment - Characterized by multiple types of seizure Side Effects - Drowsiness, Dizziness, Headache, Loss o Since it has 2 names (Lennox and Gastaut), of Appetite, Weight Loss therefore it has multiple types of seizures. - Metabolized by CYP3A4; interacts with o It is not just generalized tonic-clonic, not only drugs that induce or inhibit this enzyme absence, can have myoclonic and atonic seizure, Drug - Increased risk of metabolic acidosis therefore it’s very hard to treat, need to use Interactions when used with other carbonic multiple AEDs. anhydrase inhibitors - Patients can develop developmental delay and cognitive - Monitor: serum bicarbonate levels; impairment. Other renal function tests; cognitive side - Presentation: Tonic, atonic, myoclonic effects; hyperthermia CLOBAZAM Review: Drugs with multiple MOAs Seizure Lennox-Gastaut Syndrome (Adjunct); Refractory - Felbamate (F-all-bamate) Types Seizures (Adjunct) - Valproate (V-all-proate) - Topiramate (top of the class) - Enhances GABA-A receptor activity, - Zonisamide MOA increasing inhibitory neurotransmission and reducing neuronal excitability ABSENCE SEIZURE AEDS: - Initial Dose: 5-10 mg once daily, - Commonly occur in young individuals, particularly school- gradually increased as needed aged children (grades 1–3). Dosage - Maintenance Dose: 10-40 mg/day in - Characterized by episodes of blank staring, during which the divided doses, depending on clinical child appears to be daydreaming or inattentive, postural response tone is preserved in most cases, but it may occasionally be - A: well-absorbed orally mildly reduced. - M: primarily hepatic (CYP3A4 and - Episodes (50-100) are brief, lasting only a few seconds, and CYP2C19 pathways); produces an active Kinetics are often followed by a sudden resumption of activity as metabolite though nothing happened. - T ½: 36-42 hours (parent drug); 71-82 - Generalized seizure (No Focal Seizure because the patient is hours (active metabolite) unaware) - Respiratory depression, paradoxical - DOC for Absence seizure: Ethosuximide (not available in the agitation or aggression Philippines). Side Effects - Tolerance, dependence, cognitive - Typical Absence – 3 hertz spike and slow impairment - Atypical Absence - Drowsiness, dizziness, fatigue, ataxia - Metabolized by CYP3A4 and CYP2C19; interactions with other CYP3A4 inducers ETHOSUXIMIDE Drug or inhibitors Interactions - Additive CNS depression with other CNS Seizure Absence (Petit Mal) Seizures (First Line depressants (e.g., opioids, alcohol) Types Therapy) - Monitor: signs of sedation and - Inhibits T-type calcium channels in respiratory depression; behavioral MOA thalamic neurons, reducing abnormal Other changes; dependence; liver function neuronal firing associated with absence tests - Initial Dose: 250 mg twice daily in adults, 125 mg twice daily in children - May be used in refractory seizures. Dosage - Maintenance Dose: 500-1500 mg/day o Refractory: These are seizures that persist despite (divided doses), adjusted based on the use of multiple antiepileptic drugs (AEDs) at clinical response appropriate doses and combinations. - A: rapid and complete oral absorption - Not available in the Philippines, so other drugs are being - M: primarily hepatic; minor renal given to patients (e.g. Levetiracetam, Valproic Acid), Kinetics excretion of unchanged drug sometimes up to 4-5 AEDs and seizure is still not being - T ½: 30-60 hours in children, 40-60 controlled. hours in adults o Controlled Seizure: 1-2 seizure in a year only - Blood Dyscrasias (e.g.., Leukopenia, Agranulocytosis), Stevens-Johnson RUFINAMIDE Side Effects Syndrome - GI Discomfort, Weight Loss, Headache - Nausea, Vomiting, Drowsiness, Dizziness Seizure Lennox-Gastaut Syndrome; Focal Seizures - Administration of Ethosuximide with Types (Adjunct) Valproate ~ decrease in ethosuximide MOA - Na channel inhibitor Drug - Initial Dose: 200 mg/day (in divided clearance Interactions doses), titrated up to 800-1,600 mg/day - It may lead to toxicity, usually not Dosage combined with valproate depending on clinical response and tolerability Kinetics - M: hepatic (CYP450 enzymes) Abad | Bulaon | Fabros | Jacob | Manalili, J. | Manalili, N. | Mendoza | 11 Quia Antiseizure Pharmacology - T ½: 6 to 10 hours o Infantile Spasms - Drowsiness, fatigue, headache, nausea, o Hypsarrhythmia (seen on EEG) vomiting o Arrested development or cognitive impairment Side Effects - Irritability, behavior changes - Risk of suicidal thoughts (like other VIGABATRIN anticonvulsants) - Strong CYP3A4 inducers (e.g., Drug Infantile Spasms (First Line Treatment For carbamazepine, phenytoin) may reduce Seizure Interactions Tuberous Sclerosis Complex); Refractory rufinamide levels Types Seizures (Adjunct) - Monitor: liver functions tests; suicidal Other - Irreversible inhibition of GABA ideations or behavioral changes transaminase; ↓GABA degradation → MOA Increasing GABA levels and reducing - Not available in the Philippines excitability Review: - Infantile Spasms: 50 mg/kg/day, Drugs used for Lennox-Gastaut Syndrome titrated up as needed - Clobazam (GABA-A receptor) Dosage - Refractory Partial Seizures: Start with - Rufinamide (Sodium channel inhibitor) 500 mg twice daily, increase up to 3000 mg/day if needed DRAVENT SYNDROME - A: Well-absorbed orally; - Severe form of epilepsy, usually begins in infancy. - M: Not significantly metabolized; - Suspected in infant having persistent febrile illness. Kinetics primarily excreted unchanged in urine o Presenting symptom: benign febrile seizure + - T ½: 5-8 hours generalized tonic-clonic, myoclonic, and absence - Permanent vision loss (restricted seizure. distribution program due to risk of - Genetic Seizure: problem is in the Na channel, speciﬁcally in Side Effects visual field constriction); depression; the SCN1A mutation. drowsiness; dizziness; weight gain o Mutation disrupts normal neuronal excitability, - Few interactions as it does not rely on leading to seizures Drug hepatic metabolism - Same with Lennox-Gastaut Syndrome, this is difﬁcult to treat Interactions - May interact with other CNS because there is multiple seizure type. depressants, increasing sedation - Monito

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