Lesson 12 Antiepileptic Drugs 2024/25 PDF

Lesson 12 Antiepileptic drugs 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 SUMMARY 1. Epilepsy. introduction 2.Antiepileptic drugs 3.Benzodiazepines 4.Other uses 5. Antiepileptic drugs and women 6. Clinical uses 2  1. E...

Lesson 12 Antiepileptic drugs 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 SUMMARY 1. Epilepsy. introduction 2.Antiepileptic drugs 3.Benzodiazepines 4.Other uses 5. Antiepileptic drugs and women 6. Clinical uses 2  1. EPILEPSY. INTRODUCTION Epilepsy is a very common disorder (affects 0.5–1% of the population) – characterised by seizures, and result from episodic neuronal discharges – Often, there is no recognisable cause Not all seizures involve convulsions. - from a brief loss of attention to a full convulsive seizure lasting several minutes, as well as strange feelings or behaviour 3  1. EPILEPSY. INTRODUCTION Epilepsy is classified by the type of seizures: Partial Seizures discharge begins locally and often remains localised. Can become generalised Jacksonian epilepsy – consisting of repetitive jerking of a particular muscle group, beginning on one side of the body (thumb, big toe or angle of the mouth..)which spreads much of the body within about 2 min before dying out. The patient not necessarily lose consciousness. Psychomotor epilepsy – stereotyped purposive movements or much more complex behaviour such as dressing, walking or hair combing. 4  1. EPILEPSY. INTRODUCTION Generalised Seizures Generalised seizures involve the whole brain. Immediate loss of consciousness – tonic–clonic seizures (grand mal) – absence seizures (petit mal); – others: myoclonic, tonic, atonic and clonic seizures. 5  1. EPILEPSY. INTRODUCTION Tonic–clonic seizure tonic phase (lasts for about 1 min, during which the face becomes blue) – strong contraction of the whole musculature, involuntary cry, Respiration stops, synchronous jerks, unconsciousness. Absence seizures occur in children most frequently, the patient abruptly stops whatever he/she is doing and stares for a few seconds, with little or no motor disturbance. Lennox–Gastaut syndrome occurs in children and is associated with progressive mental retardation. Status epilepticus refers to continuous uninterrupted seizures, requiring emergency medical treatment. 6 INDEX 1. Epilepsy. introduction 2.Antiepileptic drugs 3.Benzodiazepines 4.Other uses 5. Antiepileptic drugs and women 6. Clinical uses 7  2. ANTIEPILEPTIC DRUGS. Patients with epilepsy usually need to take drugs continuously for many years, so avoidance of side effects is particularly important. Mechanism of Action: Antiepileptic drugs aim to inhibit the abnormal neuronal discharge (not the underlying cause): – 1.Enhancement of GABA action. – 2.Inhibition of sodium channel function. – 3.Inhibition of calcium channel function. More recently newer drugs with other, novel mechanisms of action have been developed. 2. ANTIEPILEPTIC DRUGS. 1. Enhancement of GABA action Phenobarbital Benzodiazepines Vigabatrin Tiagabine 10 2. ANTIEPILEPTIC DRUGS. 1. Enhancement of GABA action Phenobarbital (Luminal®, Luminaletas®) The clinical uses of phenobarbital are virtually the same as those of phenytoin, – Not often used because it causes sedation. – widely used in veterinary practice. 11 2. ANTIEPILEPTIC DRUGS. 2. Inhibition of sodium channel function Carbamazepine Phenytoin Lamotrigine Lacosamide 12 2. ANTIEPILEPTIC DRUGS Carbamazepine (Tegretol®) one of the most widely used antiepileptic drugs chemically related to the tricyclic antidepressant drugs. – Used in certain partial seizures (e.g. psychomotor epilepsy). – Treatment of neuropathic pain and manic-depressive illness Pharmacokinetics: oral administration. – Its plasma half-life is about 30 h It is a strong inducer of hepatic enzymes A slow-release preparation is used for patients who experience transient side effects 13 2. ANTIEPILEPTIC DRUGS Carbamazepine (Tegretol®) ADRs: Central Nervous System Effects:dizziness, drowsiness or sedation,confusion, ataxia (loss of coordination) Gastrointestinal Effects: nausea, vomiting, dry mouth, constipation Hematologic Effects: leukopenia,thrombocytopenia Dermatologic Effects: rash, photosensitivity Endocrine Effects: hormonal effects leading to menstrual irregularities or other endocrine disorders Liver Effects: elevated liver enzymes (transaminases), Hepatitis (rare) Allergic Reactions Treatment is usually started with a low dose, which is built up gradually to avoid dose-related toxicity. Oxcarbazepine is a carbamazepine prodrug – but less tendency to induce drug-metabolising enzymes. 14 2. ANTIEPILEPTIC DRUGS Phenytoin Structurally related to the barbiturates. widely used – effective against various forms of partial and generalised seizures not used in the absence of convulsions, could worsen the situation 15 2. ANTIEPILEPTIC DRUGS Phenytoin Pharmacokinetic Well absorbed when given orally 80–90% PP-binding Other drugs, such as salicylates, phenylbutazone and valproate, inhibit this binding competitively (interaction: may enhance or reduce the effect of the phenytoin in an unpredictable way). – increases the rate of metabolism of other drugs (e.g. oral anticoagulants- warfarin). – The metabolism of phenytoin itself can be either enhanced or competitively inhibited by various other drugs that share the same hepatic enzymes. 17 2. ANTIEPILEPTIC DRUGS Phenytoin Regular monitoring of plasma concentration has helped considerably in achieving an optimal therapeutic effect. ADRs: 18 2. ANTIEPILEPTIC DRUGS. 3.Inhibition of calcium channel function Drugs that are used to treat absence seizures: Ethosuximide Valproate Gabapentin, Pregabalin (a related analogue) They also reduce the release of various neurotransmitters and modulators. 19 2. ANTIEPILEPTIC DRUGS. Ethosuximide Selective effect on absence seizures. Mechanism of action: inhibition of T-type calcium channels Pharmacokineti is well absorbed and metabolised and, half-life of 60 h. ADRs: Its main side effects are nausea and anorexia, lethargy and dizziness. – hypersensitivity reactions (rarely). 20 2. ANTIEPILEPTIC DRUGS. Valproate (Depakine®) Useful in certain types of infantile epilepsy, – low toxicity and lack of sedative action (important!) – Used in adolescents who exhibit both tonic–clonic or myoclonic seizures as well as absence seizures. Valproate is well absorbed orally and excreted. – plasma half-life about 15 h. ADRs: 21 2. NEW ANTIEPILEPTIC DRUGS Gabapentin and Pregabalin Gabapentin – against partial seizures. – Less severe side effects – The absorption shows This makes gabapentin relatively safe. Its plasma half-life is about 6 h requiring dosing two to times daily. It is free of interactions with other drugs. It is also used as an analgesic to treat neuropathic pain. Pregabalin, an analogue of gabapentin, is more potent but otherwise very similar. – with care in patients whose renal function is impaired. 22 2. NEW DRUGS Ganaxolone and Tonabersat Ganaxolone, – positive allosteric modulator of GABA-A receptors containing δ subunits. Tonabersat – is a neuronal gap junction inhibitor. 26 INDEX 1. Epilepsy. introduction 2.Antiepileptic drugs 3.Benzodiazepines 4.Other uses 5. Antiepileptic drugs and women 6. Clinical uses 27  3.BENZODIAZEPINES Used to treat: – acute seizures, especially in children diazepam often being administered rectally – and status epilepticus for which agents such as lorazepam, diazepam, or clonazepam (IV) – act very rapidly 28 INDEX 1. Epilepsy. introduction 2.Antiepileptic drugs 3.Benzodiazepines 4.Other uses 5. Antiepileptic drugs and women 33 4. OTHER USES OF ANTIEPILEPTIC DRUGS bipolar disorder – (valproate, carbamazepine, oxcarbazepine, lamotrigine, topiramate) migraine prophylaxis – (valproate, gabapentin, topiramate) anxiety disorders – (gabapentin) neuropathic pain – (gabapentin, pregabalin, carbamazepine, lamotrigine). 34 INDEX 1. Epilepsy. introduction 2.Antiepileptic drugs 3.Benzodiazepines 4.Other uses 5. Antiepileptic drugs and women 6. Clinical uses 35 5. ANTIEPILEPTIC DRUGS AND WOMEN – may increase oral contraceptive metabolism, thus reducing their effectiveness. By inducing hepatic CYP3A4 enzymes – are thought to produce teratogenic effects. – may result in vitamin K deficiency in the newborn. 36 INDEX 1. Epilepsy. introduction 2.Antiepileptic drugs 3.Benzodiazepines 4.Other uses 5. Antiepileptic drugs and women 6. Clinical uses 37  CLINICAL USES OF ANTIEPILEPTIC DRUGS Generalised tonic–clonic seizures: carbamazepine (preferred because of a relatively favourable effectiveness :risk ratio), phenytoin, valproate newer agents include vigabatrin, lamotrigine, topiramate, levetiracetam. use of a single drug is preferred, when possible, to avoid pharmacokinetic interactions Partial (focal) seizures: – carbamazepine, valproate – alternatives include clonazepam, phenytoin, gabapentin, pregabalin, lamotrigine, topiramate, levetircetam, zonisamide. Absence seizures: – ethosuximide, valproate, lamotrigine: – valproate is useful when absence seizures coexist with tonic–clonic seizures, because most other drugs used for tonic–clonic seizures can worsen absence seizures. Neuropathic pain: – carbamazepine, gabapentin To stabilise mood in mono- or bipolar affective disorder – (as an alternative to lithium):carbamazepine, valproate 38 40 Antiepileptic drugs ANEX When to start therapy Choosing AED therapy Drugs recommendation – By seizure type – By epilepsy syndrome Maintenance of medication Drug monitoring Discontinuation of treatment  When to start AED therapy? National Institute for Health and Clinical Excellence (NICE) recommendations – AED therapy should only be started once diagnosis of epilepsy confirmed, unless exceptional circumstances – initiation of AED usually recommended after second epileptic seizure – consider AED therapy after a first unprovoked seizure if: electroencephalogram shows definite epileptic activity patient has neurologic deficit brain imaging demonstrates structural abnormality – some patients may choose not to take AED therapy after full discussion of risks and benefits 42  Choosing AED therapy National Institute for Health and Clinical Excellence (NICE) recommendations – individualize AED treatment strategy based on: epilepsy syndrome seizure type other medications and comorbidity patient's lifestyle preferences of patient, their family, and/or caregivers as appropriate – choose AED on basis of presenting epilepsy syndrome – treat patients with (monotherapy) wherever possible if initial treatment unsuccessful, switch to monotherapy with different drug caution needed during changeover period 43 RECOMMENDATIONS REGARDING SPECIFIC DRUGS USING WITH CAUTION – Carbamazepine due to possibility of causing syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia monitor sodium levels in older adults due to increased risk of SIADH – offer controlled-release carbamazepine preparations to reduce adverse effects 44  RECOMMENDATIONS REGARDING SPECIFIC DRUGS Valproate is first-line treatment for: – newly diagnosed generalized tonic-clonic seizures – newly diagnosed myoclonic seizures – tonic or atonic seizures – newly diagnosed idiopathic generalized epilepsy. – newly diagnosed juvenile myoclonic epilepsy – absence syndromes if high risk for generalized tonic-clonic seizures risk for fetal malformation! 45  Maintenance of medication Continuing AED therapy should be planned by specialist; treatment plan should include: – details of how specific drug choices were made – drug dose – possible side effects – action to take if seizures persist Adherence with treatment can be optimized by – educating patients, their families, and/or caregivers in understanding of condition and rationale of treatment – using simple medication regimens 46  Changes to AED regimen If events continue despite optimal dose of first-line AED, diagnosis of epilepsy needs to be reevaluated If AED fails due to continued seizures or adverse effects – begin second drug (which may be alternative first- or second- line drug) combination therapy (adjunctive or "add-on" therapy) should only be considered when monotherapy with AEDs is not effective. 47  Drug monitoring maintain high level of vigilance for treatment-emergent adverse effects blood monitoring – indications for monitoring of AED blood levels are determination of nonadherence suspected toxicity adjustment of phenytoin dose management of pharmacokinetic interactions specific clinical circumstances, such as – status epilepticus – organ failure – during pregnancy only if seizures increase or are likely to increase 48  Discontinuation of treatment if patient has been seizure-free for > 2 years, can discuss risks and benefits to continue or withdraw medication withdrawal of AEDs must be managed or guided by specialist Extra caution: discontinuing benzodiazepines and barbiturates (may take up to 6 months or longer) – because of possibility of seizure recurrence and/or drug-related withdrawal symptoms instruct patients, their families, and/or caregivers. 49 Questions?????