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Epilepsy.pptx
- 1. FABRIKAM RESIDENCES PHARMACOTHERAPEUTICS AND CURRENT TREATMENT GUIDELINES OF EPILEPSY Dr Abisha T Department of Pharmacology AIIMS Jodhpur
- 2. FR CONTENTS • INTRODUCTION • MECHANISM OF ACTION & PHARMACOTHERAPY OF ANTI-EPILEPTIC DRUGS • GUIDELINES FOR MANAGEMENT OF EPILEPSY IN INDIA • NEW ANTI-EPILEPTIC DRUGS • GUIDELINES FOR STATUS EPILEPTICUS • SEIZURE AND PREGNANCY • FUTURIST VIEW
- 3. FR Pharmacological Update of Clinical Guideline 20 3 EPILEPSY • Epilepsy is defined as a neurological condition characterized by recurrent epileptic seizures unprovoked by any immediately identifiable cause. • An epileptic seizure is the clinical manifestation of an abnormal and excessive discharge of a set of neurons in the brain. • Epilepsy should be viewed as a symptom of an underlying neurological disorder and not as a single disease entity. • The mainstay of treatment for epilepsy is antiepileptic drugs (AEDs) taken daily to prevent the recurrence of epileptic seizures.
- 4. FR ILAE classification of the epilepsies (2017) (International League Against Epilepsy) 5 ILAE classification of the epilepsies
- 5. FR Pharmacological Update of Clinical Guideline 20 6 CLASSIFICATION OF SEIZURES GENERALIZED SEIZURES Tonic–clonic Absence ‐ Typical ‐ Atypical ‐ Absence with special features Myoclonic absence Eyelid myoclonia Myoclonic ‐ Myoclonic ‐ Myoclonic atonic ‐ Myoclonic tonic Clonic Tonic Atonic FOCAL SEIZURES Focal Aware Focal with Impaired Awareness Focal to Bilateral Tonic- clonic UNKNOWN ‐Epileptic spasms
- 6. FR Pharmacological Update of Clinical Guideline 20 7 ETIOLOGY Genetic The direct result of a known or presumed genetic defect(s) in which seizures are the core symptom of the disorder. Structural/metabolic Structural or metabolic disorder has been demonstrated to be associated with a substantially increased risk of developing epilepsy. Structural lesions include acquired disorders such as stroke, trauma and infection. Idiopathic Nature of the underlying cause is not yet known; it may have a fundamental genetic defect at its core or it may be the consequence of an unrecognized disorder
- 7. FR Add a footer 8 MECHANISM OF ACTION & PHARMACOTHERAPY ANTI-EPILEPTIC DRUGS
- 9. FR Add a footer 10
- 10. FR American Epilepsy Society (2018) 11 ANTI-EPILEPTIC DRUGS FIRST LINE DRUGS Drug Adverse effects Contraindication & warnings Drug interaction Lamotrigine (LTG) Dizziness Ataxia Rash SJS TEN ↓ LTG by enzyme- inducing drugs like rifampin ↑ LTG by valproic acid Valproic acid (VPA) Heart burn Alopecia Weight gain Thrombocytopenia Pregnancy Hepatic disease Rifampin ↓ VPA Felbamate ↑ VPA Carbamazepine (CBZ) Sedation Diplopia Vertigo Aplastic anaemia Hepatotoxicity Induces CYP1A2, 2B6, 2C9/19, & 3A4. CBZ is inhibited by macrolides.
- 11. FR American Epilepsy Society (2018) 12 Drug Adverse effects Contraindication & warnings Drug interaction Oxcarbazepine (OXC) Dizziness Ataxia SJS TEN ↓ OXC by enzyme- inducing drugs. May increase phenytoin. Phenytoin (PHT) Gingival hyperplasia Hirsutism Pancytopenia Pregnancy ↑ PHT by isoniazid, sulfonamides, fluoxetine. ↓ PHT by enzyme- inducing drugs. Levetiracetam (LEV) Sedation Fatigue Leukopenia Suicidal ideation SJS & TEN
- 12. FR American Epilepsy Society (2018) 13 Drug Adverse effects Contraindication & warnings Drug interaction Ethosuximide (ESM) Ataxia Skin rash Renal and hepatic disease. ↓ ESM by enzyme- inducing drugs. ↑ ESM by valproic acid. Topiramate (TPM) Paraesthesia Anorexia Speech and cognitive disturbance Acute myopia Glaucoma Kidney stones ↓ TPM by enzyme- inducing drugs.
- 13. FR American Epilepsy Society (2018) 14 ALTERNATIVES Drug Adverse effects Contraindication & warnings Drug interaction Zonisamide (ZNS) Sedation Psychosis Anorexia Renal stones ↓ ZNS by enzyme- inducing drugs. Phenobarbital (PB) Tolerance Dependence Osteoporosis Hepatic encephalopathy ↑ PB by valproic acid, phenytoin. Eslicarbazepine (ESL) Hyponatremia Dizziness Sedation Diplopia Angioedema Anaphylaxis ESL induces OCs, statins and warfarin. ESL inhibits CYP2C19: ↑ PHT level
- 14. FR American Epilepsy Society (2018) 15 Drug Adverse effects Contraindication & warnings Drug interaction Brivaracetam (BRV) Sedation GI irritation Bronchial asthma ↑ carbamazepine causing decreased tolerability. May ↑ phenytoin. Primidone (PRM) Diplopia Vertigo Nystagmus Porphyria PB allergy ↑ PRM by valproic acid. ↑ PRM by phenytoin. Felbamate (FBM) Insomnia Anxiety Hypophosphatemia Blood dyscrasia hepatic dysfunction Increases phenytoin, valproic acid, active carbamazepine metabolite Lacosamide (LCM) Diplopia Vertigo Arrhythmias ↓ LCM by enzyme- inducing drugs.
- 15. FR American Epilepsy Society (2018) 16 Drug Adverse effects Contraindication & warnings Drug interaction Clonazepam (CZP) Impaired cognition Nightmares Dependence Tolerance Acute narrow angle glaucoma Significant liver disease Sensitivity to BDZs ↓ CZP by enzyme- inducing drugs. Clobazam (CLB) Depression Dependence Rash ↑ CLB by CYP2C19 inhibitors. Rufinamide (RUF) Sedation Ataxia Familial short QT syndrome Severe liver failure ↓ RUF by enzyme- inducing drugs. ↑ RUF by valproic acid.
- 16. FR American Epilepsy Society (2018) 17 Drug Adverse effects Contraindication & warnings Drug interaction Perampanel (PER) Anxiety Euphoria Agitation Homicidal ideation CBZ, OXC, PHT ↑ PER metabolism 2-3 fold. Tiagabine (TGB) Tremor Cognitive slowing Abdomen pain GI irritation ↓ TGB by enzyme- inducing drugs. Gabapentin (GBP) Dizziness Nystagmus Peripheral oedema Gi irritation
- 17. FR Add a footer 18 Selection of anti-epileptic drugs Seizure type Features First line drugs Alternatives Generalised tonic-clonic Seizure with loss of awareness and sustained contractions (tonic) of muscles throughout the body, followed by periods of muscle contraction alternating with periods of relaxation (clonic), typically lasting 1–2 min. Lamotrigine Valproic acid Zonisamide Phenytoin Levetiracetam Carbamazepine Oxcarbazepine Topiramate Phenobarbital Primidone Felbamate
- 18. FR Add a footer 19 Seizure type Features First line drugs Alternatives Focal Focal Aware Eg., clonic jerking of thumb, paresthesia of thumb. Lasting approximately 20–60 sec Lamotrigine Carbamazepine Oxcarbazepine Phenytoin Levetiracetam Zonisamide Brivaracetam Topiramate Valproic acid Tiagabine Gabapentin Lacosamide Phenobarbital Primidone Felbamate Focal with Impaired Awareness Impaired consciousness lasting 30 sec to 2 min, often associated with purposeless movements such as lip smacking or hand wringing. Focal to Bilateral Tonic-Clonic Simple or complex focal seizure evolves into a tonic-clonic seizure
- 19. FR Add a footer 20 Seizure type Features First line drugs Alternatives Typical absence Abrupt onset of impaired consciousness associated with staring and cessation of ongoing activities, typically lasting less than 30 sec. Valproic acid Ethosuximide Lamotrigine Clonazepam
- 20. FR Add a footer 21 Seizure type Features First line drugs Alternatives Atypical absence, Myoclonic, atonic A brief (perhaps a second), shock-like contraction of muscles that may be restricted to part of one extremity or may be generalized. Valproic acid Lamotrigine Topiramate Clonazepam Felbamate Clobazam Rufinamide
- 21. FR 22 PHARMACOTHERAPY • If seizure is due to metabolic disturbance (abnormality in electrolytes or glucose), reverse the derangement. • If seizure is due to structural CNS lesion (brain tumour, vascular malformation or brain abscess), remove the lesion. • Anti-epileptic therapy is not required unless subsequent seizures occur in the absence of these precipitants. TREATMENT OF UNDERLYING CONDITIONS • Universal precipitating factor is sleep deprivation. • Others are individual specific such as alcohol intake, video game monitor, music or individual’s voice. • Stress reduction techniques such as physical exercise, meditation or counseling may be helpful. AVOIDANCE OF PRECIPITATING FACTORS
- 22. FR Add a footer 23 ANTIEPILEPTIC DRUG THERAPY Overall goal is to completely prevent seizures without causing any untoward side effects, preferably with a single medication and a dosing schedule that is easy for the patient to follow. WHEN TO INITIATE ANTIEPILEPTIC DRUG THERAPY Antiepileptic drug therapy should be started in any patient with recurrent seizures of unknown etiology or a known cause that cannot be reversed. Generally accepted risk factors associated with recurrent seizures include the following: (1) an abnormal neurologic examination. (2) seizures presenting as status epilepticus. (3) postictal Todd’s paralysis. (4) a strong family history of seizures. (5) an abnormal EEG. Most patients with one or more of these risk factors should be treated. SELECTION OF ANTIEPILEPTIC DRUGS Worldwide phenytoin, valproic acid, carbamazepine, phenobarbital and ethosuximide are used as first-line therapy for most seizure disorders. Most of the new drugs are used as add-on or alternative therapy, although many are now being used as first-line monotherapy. In addition to efficacy, convenience of dosing and potential side effects influence the choice of medication. Recent advance in the care of patients with epilepsy is application of genetic testing to help guide the choice of therapy. For eg, patients with mutations in the sodium channel subunit SCN1A should generally avoid taking phenytoin or lamotrigine.
- 23. FR Add a footer 26 INITIATION AND MONITORING OF THERAPY • Determination of the optimal dose is often a matter of trial and error. • Most antiepileptic drugs need to be introduced relatively slow to minimize side effects. • Patients should expect that minor side effects such as mild sedation, slight changes in cognition or imbalance will typically resolve within a few days. • Starting doses are usually the lowest value. • Subsequent increases should be made only after achieving a steady state with the previous dose (i.e., after an interval of ≥ 5 t½ ). • Therapeutic ranges of serum drug concentrations are only an approximate guide for determining the proper dose for a given patient. • The key determinants are the clinical measures of seizure frequency and presence of side effects, not the laboratory values.
- 24. FR Add a footer 27 • If seizures continue despite gradual increases to the maximum tolerated dose, Switch to another antiepileptic drug. This is usually done by maintaining the patient on the first drug while a second drug is added Dose of the 2nd drug should be adjusted to decrease seizure frequency without causing toxicity Once this is achieved, the first drug can be gradually withdrawn (usually over weeks) • The dose of the second drug is then further optimized based on seizure response and side effects. Monotherapy should be the goal whenever possible.
- 25. FR Add a footer 28 WHEN TO DISCONTINUE THERAPY • Overall, about 50–60% of patients who have their seizures completely controlled with antiepileptic drugs can eventually discontinue therapy. • The following patient profile yields the greatest chance of remaining seizure free after drug withdrawal: (1) complete medical control of seizures for 1–5 years. (2) single seizure type, with generalized seizures having a better prognosis than focal seizures. (3) normal neurologic examination, including intelligence. (4) no family history of epilepsy. (5) normal EEG. • Attempt withdrawal of therapy after 2 years in a patient who meets all of the above criteria. • It is preferable to reduce the dose of the drug gradually over 2–3 months. • Most recurrences occur in the first 3 months after discontinuing therapy and patients should avoid driving or swimming during this period.
- 26. FR Add a footer 29 TREATMENT OF REFRACTORY EPILEPSY • Approximately 1/3rd of patients with epilepsy requires combination of drugs to control seizures. • Patients who have focal epilepsy due to an underlying structural lesion or with multiple seizure types and developmental delay are particularly likely to require multiple drugs. • Initial combination therapy combines first-line drugs (carbamazepine, oxcarbazepine, lamotrigine, valproic acid, levetiracetam and phenytoin). • If these drugs are unsuccessful, then the addition of zonisamide, brivaracetam, topiramate, lacosamide or tiagabine is indicated. • Patients with myoclonic seizures resistant to valproic acid, respond to clonazepam or clobazam and those with absence seizures may respond to a combination of valproic acid and ethosuximide. • If there is no improvement, a third drug can be added while the first two are maintained. • If there is a response, the less effective or less tolerated of the first two drugs should be gradually withdrawn.
- 27. FR Add a footer 30 GUIDELINES FOR MANAGEMENT OF EPILEPSY IN INDIA
- 28. FR Indian epilepsy society 31
- 29. FR Indian epilepsy society 32
- 30. FR Indian epilepsy society 33
- 31. FR American Epilepsy Society Guidelines (2018) 34 NEW ANTI-EPILEPTIC DRUGS FOR NEW ONSET EPILEPSY Indication New drug Conventional drug ≥60 years with new-onset focal epilepsy Lamotrigine Carbamazepine-immediate release Gabapentin New-onset focal epilepsy Levetiracetam Carbamazepine-controlled release Zonisamide
- 32. FR American Epilepsy Society (2016) 35 ALGORITHM FOR STATUS EPILEPTICUS
- 33. FR American Epilepsy Society (2016) 36
- 34. FR Add a footer 37 SEIZURE AND PREGNANCY • Seizure frequency during pregnancy increase in ~30%. • The overall incidence of fetal abnormalities in children born to mothers with epilepsy is 5–6%. • The risk increases with the number of medications used. • Most common malformations associated are defects in the cardiovascular and musculoskeletal system. • Valproic acid is strongly associated with an increased risk of adverse fetal outcomes.
- 35. FR Add a footer 38 • The newer antiepileptic drugs are far safer, except for topiramate. • Monotherapy at the lowest effective dose is usually preferred, especially during the first trimester. • Patients should also take folate (1–4 mg/d), although the benefits of this treatment remain unproved. • Enzyme-inducing drugs such as phenytoin, carbamazepine, oxcarbazepine, topiramate, phenobarbital and primidone cause a transient and reversible deficiency of vitamin K–dependent clotting factors in ~50% of newborn. • Mother should be treated with oral vitamin K (20 mg/d) in the last 2 weeks of pregnancy, and the infant should receive intramuscular vitamin K (1 mg) at birth.
- 36. FR American Epilepsy Society (2017) 39 FUTURIST VIEW
- 37. FR Add a footer 40 THANK YOU