Seizures.pdf

01 41 0) SEIZURES i( ID :1 Evaluating Exam Preparatory Course ❑ Seizures High Priority Quiz 1 Za hr av ❑ Seizures High Priority Quiz 2 la 1 ❑ Seizures High Priority Quiz 3 to Li ce ns ed AED: Anti-Epileptic Drug CBZ: Carbamazepine ETHO: Ethosuximide GBP: Gabapentin LEV: Levetiracetam...

01 41 0) SEIZURES i( ID :1 Evaluating Exam Preparatory Course ❑ Seizures High Priority Quiz 1 Za hr av ❑ Seizures High Priority Quiz 2 la 1 ❑ Seizures High Priority Quiz 3 to Li ce ns ed AED: Anti-Epileptic Drug CBZ: Carbamazepine ETHO: Ethosuximide GBP: Gabapentin LEV: Levetiracetam LTG: Lamotrigine PB: Phenobarbital PER: Perampanel PHT: Phenytoin PRM: Primidone TOP: Topiramate VPA: Valproic Acid (or divalproex) Le y LEGEND Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 2 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 1 WHAT IS EPILEPSY? What is the difference between seizures and epilepsy? Patients are diagnosed with epilepsy if they fulfill any of the following three criteria: 01 41 0) 1. A history of 2 unprovoked seizures over 24 hours apart :1 2. A history of 1 unprovoked seizure, and a > 60% chance of having another seizure in the next 10 years Za hr av i( ID 3. A history of 1 unprovoked seizure, and a clearcut epilepsy syndrome demonstrated by electroencephalogram (EEG) abnormalities Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. la 3 Le y WHAT IS THE PATHOPHYSIOLOGY OF EPILEPSY? to • Seizures are thought to result from a network of abnormally excitable neurons firing in synchronization ns ed • Hyperexcitability has been linked to the increased disposition of neurons to depolarize and propagate action potentials • This depolarization is significantly influenced by potassium, calcium, sodium, and chloride channels in the neuronal membrane ce • Many anti-epileptic agents target these channels, reducing sodium influx or increasing chloride influx to hyperpolarize the neuron and prevent firing Li • Other potential mechanisms of epilepsy have been proposed, such as the upregulation of Synaptic Vesicle protein 2A (SV2A), a target of the newer generation of anti-epileptics (not completely understood) Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 4 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 2 WHAT ARE EXAMPLES OF DRUG AND NON-DRUG CAUSES OF SEIZURES? Premature birth with low gestational weight • Perinatal injury • History of seizures from alcohol withdrawal • History of febrile seizures • Family history of seizures • Stroke • Head trauma • Infections (HIV, Zika virus, cytomegalovirus) • Seizures may be precipitated by known triggers such as stress, photostimulation (rapidly flashing lights or changing images), hyperventilation, sleep deprivation, and hormonal changes occurring around menses, puberty, or pregnancy • The following medications lower the seizure threshold: alcohol, antidepressants (most notably bupropion), high-dose phenothiazines, opioids, stimulants (e.g. amphetamines, cocaine), theophylline, withdrawal from substances (e.g. alcohol, benzodiazepines, and anti-epileptic drugs) Za hr av i( ID :1 01 41 0) • Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. la 5 ✓ Optimize quality of life to ✓ Prevent seizure recurrence Le y WHAT ARE THE GOALS OF THERAPY? When can antiepileptic therapy be discontinued? After 2-4 years of achieving seizure freedom Li ce ns ed ✓ Prevent or minimize side effects of anti-epileptic drugs Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 6 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 3 WHAT ARE THE DEFINITIONS OF SEIZURE-RELATED TERMS? Seizure threshold describes an individual’s risk of experiencing a seizure, where a reduced seizure threshold means that a patient is at a higher risk of experiencing a seizure Postictal Period of time following a seizure where consciousness or behaviour is altered from baseline MOTOR SIGNS 01 41 0) Seizure threshold Automatic behaviours such as lip smacking or chewing Atonic Loss of muscle tone, limpness Clonic Sustained rhythmic jerking or twitching (usually affecting the arm, shoulder, face, or leg) Spasm An involuntary muscle contraction (tightening of a muscle) such as trunk flexion Tonic Muscle stiffening (becoming rigid) Hyperkinetic Abnormal involuntary excessive movements that can be rhythmic, brief and random, or even jerk-like; thrashing or pedaling movements Myoclonic Sudden, non-rhythmic, and brief involuntary movement (e.g. jerking of arm, shoulder, face, or leg) Za hr av i( ID :1 Automatisms Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. la 7 Relating to autonomic nervous system; involuntary physiological responses such as sweating and salivation ns ed Autonomic to NON-MOTOR SIGNS Le y WHAT ARE THE DEFINITIONS OF SEIZURE-RELATED TERMS? Behaviour Arrest Pausing or freezing of behaviour Sensory Feelings of fear, joy, anger, or depression. ce Emotion Language, thinking, or memory problems (feeling of deja vu). Feelings of numbness, tingling, hearing sounds, altered tastes, seeing visions Li Cognitive Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 8 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 4 WHAT ARE THE FEATURES OF FOCAL (PARTIAL) SEIZURES? • Originate from a neural network in only one side of the brain PRESENTATION Without impaired awareness (simple partial) • Aware of themselves and their environment • Motor and/or non-motor (e.g. autonomic, sensory, cognitive) components • Short duration, usually <1 minute With impairment of awareness (complex partial) • • • • • • Focal to bilateral tonic-clonic seizures (secondarily generalized tonicclonic seizures) • Seizures originating from a smaller area within one side of the brain that progress and affect a wider area that spans both brain hemispheres • Starts as focal seizure with impaired awareness but progresses to bilateral convulsive features such as tonic-clonic spasms 01 41 0) TYPE OF SEIZURE Za hr av i( ID :1 Impaired awareness at any point during seizure (can occur later in the seizure) May not recall events of seizure, postictal confusion common Motor and/or non-motor symptoms Motor features usually are automatisms Non-motor features usually manifest as behavioural arrest (blank stare) Usually lasts 1-2 minutes Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. la 9 Le y WHAT ARE THE FEATURES OF GENERALIZED SEIZURES? SEIZURE TYPE to • Originate from a neural network encompassing both sides of the brain PRESENTATION Sudden onset and short-lived (5-10 seconds) Manifests as behavioural arrest (blank stare); usually affects children No warning signs or postictal consequences May show upwards rolling of eyeballs and eyelid fluttering (eyelid myoclonia) Non-motor: atypical absence seizures Slightly slower onset and longer lasting (~20 seconds) Accompanied by motor features such as myoclonic muscle movements or automatisms; common in children May show upwards rolling of eyeballs and eyelid fluttering (eyelid myoclonia) ns ed • Non-motor: typical absence (“petit mal”) • • seizures • ce • • Li • Motor: generalized tonic-clonic (“grand mal”) seizures • • • Classic, well-known seizure presentation with muscle stiffening in the tonic phase, and rhythmic jerking motions in the clonic phase Lasts ~1-2 minutes Postictal confusion, fatigue, drowsiness, and amnesia are common Motor: myoclonic seizures • • Brief, bilateral jerking movements Individual usually remains conscious and alert Motor: atonic seizures • Sudden loss of muscle tone manifesting as “drop-attacks” (loses muscle tone and may slump); common in children; postictal confusion may be present Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 10 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 5 WHAT IS THE GENERAL TREATMENT ALGORITHM? 01 41 0) ↑dose AED and monitor for dosedependent side effects :1 Initiate low-dose AED monotherapy If inadequate relief from AED, add 2nd AED and titrate to desired dose Slowly decrease and discontinue dose of 1st AED Za hr av i( ID Choice of Anti-Epileptic Drug (AED) is based on seizure type, comorbidities, potential for drug interactions, side effect profile. Note, AED polytherapy is reserved for patients who fail to achieve acceptable control on 2-3 monotherapy drugs Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. la 11 ns ed 1st line monotherapy to Le y WHAT ARE THE ANTIEPILEPTICS OF CHOICE FOR FOCAL SEIZURES? ce • Carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, valproic acid Li Alternative or adjunctive therapy • Brivaracetam, clobazam, eslicarbazepine, gabapentin, lacosamide, perampanel, phenobarbital, phenytoin, primidone, topiramate, vigabatrin Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 12 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 6 WHAT ARE THE ANTIEPILEPTICS OF CHOICE FOR TONIC-CLONIC GENERALIZED SEIZURES? 01 41 0) 1st line monotherapy • Valproic acid (superior to lamotrigine and topiramate, but avoid in women and girls of childbearing potential), lamotrigine, levetiracetam, oxcarbazepine, carbamazepine :1 Alternative or adjunctive therapy Za hr av i( ID • Clobazam, topiramate Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. la 13 ns ed 1st line monotherapy to Le y WHAT ARE THE ANTIEPILEPTICS OF CHOICE FOR TONIC OR ATONIC GENERALIZED SEIZURES? ce • Valproic acid (superior to lamotrigine and topiramate, but avoid in women and girls of childbearing potential) Li Alternative or adjunctive therapy • Lamotrigine, rufinamide, topiramate Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 14 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 7 WHAT ARE THE ANTIEPILEPTICS OF CHOICE FOR ABSENCE GENERALIZED SEIZURES? - 1st line monotherapy 01 41 0) • Ethosuximide (1st option if only absence seizures present due to lower rates of attention difficulties and behavioural problems compared to valproic acid) • Valproic acid (offer 1st if high risk of tonic-clonic seizure and not female of childbearing age) • Lamotrigine (less effective, use only if other 1st line options are not suitable) Alternative or adjunctive therapy i( ID Therapies to avoid (can exacerbate seizures) • Carbamazepine, gabapentin, oxcarbazepine, phenytoin, vigabatrin Za hr av [ :1 • Clobazam, levetiracetam, topiramate Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. la 15 · Le y WHAT ARE THE ANTIEPILEPTICS OF CHOICE FOR MYOCLONIC GENERALIZED SEIZURES? to First-line monotherapy ns ed • Valproic acid (most effective but avoid in women and girls of childbearing potential), levetiracetam, topiramate ce Alternative or adjunctive therapy Li • Clobazam Therapies to avoid (can exacerbate myoclonic seizures) AAA • Carbamazepine, gabapentin, oxcarbazepine, phenytoin, vigabatrin Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 16 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 8 HOW IS STATUS EPILEPTICUS TREATED? • Status epilepticus describes recurrent generalized tonic-clonic seizures that last more than 30 minutes, or intermittent seizures lasting more than 30 minutes without fully recovering consciousness • Episodes of suspected status epilepticus require immediate treatment 01 41 0) • Most seizures that last 5 minutes or longer are not likely to resolve on their own, and status epilepticus should be suspected • Treatments indicated change based on the time since symptom onset and include supportive care, thiamine, dextrose, IV lorazepam (alternatively: IM midazolam or rectal diazepam) IV phenytoin, IV midazolam, or IV propofol • Benzodiazepines, phenytoin, and propofol are used to stop the seizure :1 • Dextrose is used to treat any suspected hypoglycemia, as severe hypoglycemia can lead to seizures Za hr av i( ID • Thiamine is used to minimize the risk of Wernicke’s encephalopathy, which is caused by thiamine deficiency and can be exacerbated if dextrose (or glucose) is administered alone Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. la 17 Le y WHICH ANTIEPILEPTICS CAUSE DOSE-RELATED CNS AND GI ADVERSE EFFECTS? to • Most likely to occur when patients are initiated on AED therapy, and when doses of their AEDs are increased ns ed • Resolve on their own within a few weeks of starting the AED or modifying the dose Li ce • If the adverse effects are suspected to be related to a medication’s peak dose (usually 30-60 minutes after each dose, but may vary based on individual agents’ pharmacokinetics), different measures may be taken to reduce the peak dose, such as switching to a controlled-release formulation, or by administering the AED more frequently at lower doses Carbamazepine, lamotrigine, primidone, tiagabine, topiramate, and valproic acid have the highest potential of causing CNS and gastrointestinal effects Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 18 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 9 WHICH ANTIEPILEPTICS ARE ASSOCIATED WITH RASHES? • While the rash usually presents in the first 6-8 weeks of treatment, it can occur at any time during therapy. • Patients who develop a rash while taking any AED are at a higher risk of developing another rash with phenytoin, carbamazepine, or lamotrigine i( ID • Human Leukocyte Antigen (HLA) testing may be warranted in individuals of Han Chinese or Japanese descent before initiating carbamazepine, as these individuals are likely to carry variations of the HLA alleles that are strongly associated with the risk of SJS/TEN when taking carbamazepine 01 41 0) • When a patient develops a rash thought to be caused by AED use, immediate AED cessation is warranted. Idiosyncratic side effect that can result from the use of any AED but is mostly observed with carbamazepine, lamotrigine (major concern), and phenytoin :1 • May develop into life-threatening conditions, such as Stevens Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN) Za hr av • In addition, those who develop a rash while taking carbamazepine have a higher risk of developing a rash with oxcarbazepine and eslicarbazepine due to cross-sensitivities. Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. la 19 Le y WHICH CHRONIC SIDE EFFECTS ARE ENZYME-INDUCING ANTIEPILEPTICS ASSOCIATED WITH? Li ce ns ed to • Associated with alterations in endocrine function resulting in osteoporosis/decreased bone mineral density (increased risk of fractures), lower fertility, thyroid dysfunction, and hyperlipidemia Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 20 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 10 WHICH ANTIEPILEPTICS ARE ASSOCIATED WITH HYPONATREMIA (DECREASED SERUM SODIUM LEVELS)? 01 41 0) Associated with oxcarbazepine, carbamazepine, and eslicarbazepine Za hr av i( ID :1 • Characteristics that increase a patient’s risk of developing hyponatremia include old age, use of multiple concomitant antiepileptic drugs, use of antihypertensive medication (especially diuretics), high serum levels of carbamazepine or oxcarbazepine, and a history of hyponatremia during a previous drug trial Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. la 21 ns ed Weight gain to Le y WHICH ANTIEPILEPTICS ARE ASSOCIATED WITH CHANGES IN WEIGHT? ce • Carbamazepine, valproic acid, perampanel, gabapentin, vigabatrin Li Weight loss • Ethosuximide, topiramate Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 22 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 11 HOW DO ANTIEPILEPTICS AFFECT HEPATIC ENZYMES? ↑ metabolism DOC Proges , Estrogen = • PER (>12 mg/day) • PB Phenobarbital · • PHT Phenytoin • PRM primidora • Rufinamide • TOP (>200 mg) topiromate Etha Depot progestione - L Brivaracetam Clobazam a ETHO in GBP Lacosamide LTG Lamotrigive LEV Levetrisetum acid VPA valopita Vigabatrin Za hr av & Hormonal · Barrier Copyright © 2023 PharmAchieve Corporation Ltd. · Private and Confidential. + non-HormonalIVD contraceptives la 23 01 41 0) • Oxcarbazepine • • • • • • • • • :1 • Eslicarbazepine i( ID I • CBZ Non-enzyme-inducing AED Enzyme-inducing AED Al , GT to Phenobarbital Le y WHAT ARE THE PROPERTIES OF BARBITURATES? CNS, hyperactivity Chronic side effects Behavioural and cognitive problems, mood changes, sedation, depression, diminished libido ce Rash Li Idiosyncratic side effects ns ed [ ]-dependent side effects Metabolic pathways? Comments? Primidone CNS, behavioural changes Behavioural and cognitive problems, sedation, connective tissue disorders, depression, diminished libido • Rash • • • Metabolism: CYP 2C9/19 Induces: CYP 1A2/2C/3A4 25% renal elimination • • • Metabolism: CYP 2C9/19 Induces: CYP 1A2/2C/3A4 40-50% renal elimination • • • Long half-life (once daily dosing) VPA inhibits metabolism ↓efficacy of hormonal contraceptives • Metabolized to PB (PRM also has clinical effects) VPA inhibits metabolism ↓efficacy of hormonal contraceptives • • Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 24 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 12 WHAT ARE THE PROPERTIES OF BENZODIAZEPINES? Clobazam CNS Chronic side effects Depression Idiosyncratic side effects N/A • Tolerance develops i( ID Za hr av Comments? :1 • Few drug interactions Metabolized by 3A4, 2C19, 2B6 Inhibits: 2D6 Induces: 3A4 (weak) 2 metabolites: norclobazam is an active metabolite with 1/4th potency compared with parent versus 4-hydroxyclobazam which is the inactive metabolite Metabolites eliminated renally (94%) • • • • • Metabolic pathways? 01 41 0) [ ]-dependent side effects Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. la 25 Le y WHAT ARE THE PROPERTIES OF CARBOXYLIC ACID DERIVATIVES? to Valproic acid/divalproex ns ed [ ]-dependent side effects CNS, GI upset, tremor, thrombocytopenia PCOS, weight gain, hyperammonemia, menstrual cycle abnormalities, osteoporosis Idiosyncratic side effects Hepatic toxicity, pancreatitis, alopecia, blood dyscrasias, thrombocytopenia Metabolic pathways? • • Inhibits: CYP2C9,3A Renal elimination: 2% Comments? • Teratogenic – avoid in women of childbearing potential Li ce Chronic side effects Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 26 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 13 WHAT ARE THE PROPERTIES OF GAMMA AMINOBUTYRIC ACID (GABA) DERIVATIVES? Vigabatrin CNS, tremors, vision changes CNS, permanent vision loss Chronic side effects Weight gain, tremors, vision changes Permanent vision loss Idiosyncratic side effects Pedal edema Anemia, peripheral neuropathy, weight gain, hyperactivity, mood changes (e.g. depression) Metabolic pathways? Renal elimination: 90% Renal elimination (unchanged): 80% • • :1 • Few interactions, BID dosing, no dermatologic, hepatic, or hematologic effects Permanent visual field defects limits use May worsen absence or myoclonic seizures • • Za hr av Comments? Can use in liver failure (not metabolized hepatically) No significant drug interactions TID dosing i( ID • 01 41 0) Gabapentin [ ]-dependent side effects Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. la 27 CNS, dose-related encephalopathy ns ed [ ]-dependent side effects to Phenytoin Le y WHAT ARE THE PROPERTIES OF HYDANTOIN DERIVATIVES? ce Chronic side effects Li Idiosyncratic side effects Behavioural problems, skin thickening, folate deficiency, gingival hyperplasia, hiuritism, coarsening of facial features (acne), cognitive impairment, metabolic bone disease/osteoporosis, nystagmus, increased liver enzymes Blood dyscrasias, rash (rarely severe) Metabolic pathways? • • • Metabolism: 2C9/19, 3A4 Induced: 1A2/2C/3A4 Renal elimination: 5% Comments? • • • Dosing is complicated by saturation kinetics Therapeutic serum concentration range: 10-20 mg/: (40-80 μmol/L) Daily or BID dosing Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 28 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 14 WHAT ARE THE PROPERTIES OF IMINOSTILBENE DERIVATIVES? Oxcarbazepine CNS (e.g. ataxia, nystagmus), hyponatremia CNS Chronic side effects Hyponatremia Hyponatremia Idiosyncratic side effects Rash, blood dyscrasias, hepatotoxicity Rash Metabolic pathways? • Metabolism: CYP3A4 • Induces: 1A2/2C/3A4 • <1% renal elimination • Metabolism: CYP3A4 • Induces: CYP3A4 (weak) • Inhibits: CYP2C19 :1 • Similar to CBZ with higher risk of hyponatremia Skin rash cross-reactivity with CBZ Efficacy similar to CBZ but better tolerated (no autoinduction of enzymes) i( ID IR or CR dosing Take with food Linear pharmacokinetics May worse absence seizures, exacerbate/produce myoclonus • • Za hr av Comments? • • • • 01 41 0) Carbamazepine [ ]-dependent side effects Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. la 29 to Ethosuximide Le y WHAT ARE THE PROPERTIES OF SUCCINIMIDE DERIVATIVES? Chronic side effects Behavioural problems Li Comments? Rash, blood dyscrasias ce Idiosyncratic side effects Metabolic pathways? ns ed [ ]-dependent side CNS, GI upset effects • Metabolism: CYP3A4 • Renal elimination: 12-20% • Few drug interactions - Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 30 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 15 WHAT ARE THE PROPERTIES OF LACOSAMIDE, LAMOTRIGINE, AND LEVETIRACETAM? pregnancy C Lamotrigine(g Lacosamide ↓ Levetiracetam CNS, behavioural problems, nausea, weakness [ ]-dependent side effects CNS, increased PR interval on ECG Chronic side effects Behavioural problems Idiosyncratic side effects Increased LFTs Rash (SJS) Metabolic pathways? • Metabolism: CYP2C, 3A4 • Renal elimination: 70% Renal elimination: 10% Caution in patients with cardiac conduction abnormalities • Very slow titration • Addition of hormonal contraceptives (COC) reduces LTG serum levels by Rapid titration up to 50%: consider doubling LTG dose after starting COC 01 41 0) CNS, rash, possibly insomnia - - Psychosis Za hr av Comments? i( ID :1 Renal elimination: 66% Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. la 31 Perampanel Le y WHAT ARE THE PROPERTIES OF PERAMPANEL, AND RUFINAMIDE? CNS, behavioural changes Chronic side effects Weight gain ns ed ce Idiosyncratic side effects to [ ]-dependent side effects - Metabolism: CYP3A4/3A5 Induces: 2B6/3A4 (weak) Inhibits CYP2C8/3A4 (weak) Renal elimination: 22% Comments? • Serious psychiatric effects in patients with/without history of psychiatric conditions • Monitor during titration and at high doses • Avoid consuming alcohol • Decreases efficacy of levonorgestrelcontaining hormonal contraceptives Li Metabolic pathways? • • • • Rufinamide CNS, GI, Multi-organ hypersensitivity, status epilepticus, leukopenia, QT shortening • Induces: CYP3A4 (weak) • Inhibits: CYP2E1 (weak) • Renal elimination: 2% • Indicated as adjunct in generalized seizures in LennoxGastaut syndrome Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 32 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 16 WHAT ARE THE PROPERTIES OF TOPIRAMATE? Topiramate CNS Chronic side effects Weight loss, kidney stones, osteoporosis Idiosyncratic side effects Metabolic acidosis, acute angle glaucoma, oligohydrosis, paresthesias Metabolic pathways? • Induces: CYP3A4 • Inhibits: 2C19 • Renal elimination: 70% Comments? • Cognitive effects limits use • Requires slow titration Za hr av i( ID :1 01 41 0) [ ]-dependent side effects Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. la 33 Le y WHAT ARE THINGS TO CONSIDER IN PREGNANT AND BREASTFEEDING PATIENTS? to • Lamotrigine levels can drop by >50% during 2nd and 3rd trimesters of pregnancy (thus increases doses by >100% as necessary) and measure serum levels monthly during pregnancy ns ed • Note, lamotrigine levels rise quickly after delivery (within 1-2 weeks) thus doses must be adjusted early after delivery to avoid toxicity • Levetiracetam levels may also drop during pregnancy (consider monitoring serum levels in patients susceptible to small changes in serum levels) ce • Enzyme-inducing AEDs may increase fetal vitamin K degradation thus vitamin K is routinely administered to newborns after delivery to prevent hemorrhagic diseases Li • Breastfeeding should not be discouraged The drug of choice should ultimately be the drug that best controls seizures! Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 34 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 17 REFERENCES 8. 9. 10. 11. 12. 13. Za hr av 14. 15. 01 41 0) 7. :1 2. 3. 4. 5. 6. Nguyen, V.V., Dergalust, S., & Chang, E. Epilepsy. In: DiPiro, J.T., Yee, G.C., Posey, L.M., Haines, S.T., Nolin, T.D., Ellingrod, V. Pharmacotherapy: A Pathophysiologic Approach. 11th edition. McGraw Hill. Moeller, J.J. and Sadler R.M. Seizures and Epilepsy. In: Compendium of Therapeutic Choices. Canadian Pharmacists Association. Kiriakopoulos, E. and Osborne Shafer, P. Absence Seizures. Epilepsy Foundation. Bromfield, E.B. Drugs that May Lower Seizure Threshold. Epilepsy Foundation. Perucca, E. and Tomson, T. The pharmacological treatment of epilepsy in adults. Lancet Neurol. 2011;10: 446-456. Fisher R.S., Cross, J.H., French, J.A., et al. Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):522-530. Krumholz A., Wiebe S., Gronseth, G.S. et al. Evidence-based guideline:management of an unprovoked first seizure in adults:report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2015;84(16):1705-13. Glauser T., Shinnar S., Gloss D. et al. Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the Guidelines Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48-61. French J.A., Pedley T.A. Initial Management of Epilepsy. N Engl J Med. 2008;359(2):166-76. Scottish Intercollegiate Guidelines Network. Diagnosis and management of epilepsy in adults. National Institute for Health and Care Excellence. Epilepsies: diagnosis and management. National Institute for Health and Care Excellence. Surveillance Report 2018 - Epilepsies: diagnosis and management (2012) NICE guideline CG137. Kanner A.M., Ashman, E., and Gloss, D. 2018. Practice Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology;91:74-81. doi:10.1212/WNL.0000000000005755. Ontario Epilepsy Guidelines. Clinical Guidelines for the Management of Epilepsy in Adults and Children. Schachter SC. Antiseizure medications: Mechanism of action, pharmacology, and adverse effects. In: Post T, ed. UpToDate. UpToDate. i( ID 1. Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. la 35 to Li ce ns ed August 9, 2023 • Content reviewed; no changes made Le y CHANGE LOG Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 36 Copyright © 2023 PharmAchieve Corporation Ltd. Private and Confidential. 18