Antiepileptic drugs

Antiepileptic drugs

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  Antiepileptic drugs Dr. KarunKumar Assistant Professor Dept. of Pharmacology
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  Definitions • Seizure (from the Latin sacire, “to take possession of ”) is a transient occurrence of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain • Epilepsy  Condition in which a person has a risk of recurrent seizures due to a chronic, underlying process. Clinical phenomenon rather than a single disease entity.
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  Types of seizures •Focal seizures  Originate within networks limited to one brain region (partial seizures NO longer used) • Generalized seizures  Arise within and rapidly engage networks distributed
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  Classification of seizures(2017 ILAE) 1. Focal Onset (having intact or impaired awareness, motor or nonmotor onset, or evolve from focal to bilateral tonic clonic) 2. Generalized Onset a. Motor  Tonic-clonic, Other motor (e.g., atonic, myoclonic) b. Nonmotor (absence) 3. Unknown Onset a. Motor, nonmotor, or unclassified
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  Classification of AED
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  Exam diagram
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  Excitatory synapse
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  Inhibitory synapse
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  Approach to thepatient • History and examination • 1st goal  Determine whether the event was truly a seizure • In-depth history is essential, because in many cases the diagnosis of a seizure is based solely on clinical grounds—the examination and laboratory studies are often normal
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  Plan of action LFT,RFT
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  AED
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  PNES or PNEE •Pseudoseizures, psychogenic seizures, and hysterical seizures are older terms • Clinically resemble epileptic seizures but occur without the excessive synchronous cortical electroencephalographic activity that defines epileptic seizures • These terms reinforce the idea that the events are not epileptic seizures and are of psychiatric origin
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  Phenytoin • MOA Prevents repetitive detonation of normal brain cells (↑ inact. state of VGSC) • Also, 1. ↓ presynaptic release of glutamate 2. ↑ GABA release 3. ↓ Ca2+ influx
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  Adverse effects-PHENYTOIN • Plasmalevel monitoring needed (0 order k.) • Hypertrophy of gums • Enzyme induction • Neutropenia and other hypersensitivity reactions • Young girls beware ! Causes hirsutism, coarsening of facial features and acne • Teratogenic • Osteomalacia
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  • Interference withfolate absorption leads to megaloblastic anemia • Neurological manifestations at higher doses  Ataxia, vertigo, nystagmus, diplopia
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  Uses • Used onlywhen better tolerated newer drugs cannot be used • Trigeminal neuralgia  2nd choice drug to Carbamazepine
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  Interactions 1. Phenobarbitone competitivelyinhibits phenytoin metabolism, while by enzyme induction both enhance each other’s degradation— unpredictable overall interaction 2. Carbamazepine and phenytoin induce each other’s metabolism 3. Valproate displaces protein bound phenytoin and decreases its metabolism  Plasma level of unbound phenytoin increases
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  4. Chloramphenicol, Isoniazid,Cimetidine and Warfarin inhibit phenytoin metabolism  Can precipitate its toxicity 5. Phenytoin induces microsomal enzymes and increases degradation of steroids (failure of oral contraceptives), Doxycycline, Theophylline
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  Fosphenytoin • Water solubleprodrug of Phenytoin has been introduced to overcome the difficulties in i.v. administration of Phenytoin, which it has replaced for use in status epilepticus. • On i.v. injection it is less damaging to the intima • While Phenytoin cannot be injected in a drip of glucose solution (because it gets precipitated), fosphenytoin can be injected with both saline and glucose
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  Carbamazepine • 1st lineAED for focal seizures and trigeminal neuralgia (MOA  ↑ inact. state of VGSC) • Manic depressive illness and acute mania  As an alternative to Lithium • Carbamazepine produces dose-related neurotoxicity  sedation, dizziness, vertigo, diplopia and ataxia • Hypersensitivity  Rashes, photosensitivity, hepatitis, lupus like syndrome and rarely agranulocytosis, aplastic anemia
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  Lupus like syndrome •Autoimmune disorder caused by a reaction to certain medications • Symptoms are muscle and joint pain sometimes with swelling;flu-like symptoms of fatigue and fever • SHIP drugs are responsible 1. Sulfonamides incl. dapsone and PAS 2. Hydralazine 3. Isoniazid 4. Procainamide
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  Interactions • Carbamazepine isan enzyme inducer; can reduce efficacy of Haloperidol, oral contraceptives • Metabolism of Carbamazepine is induced by Phenobarbitone, Phenytoin, Valproate and vice versa • Erythromycin, Fluoxetine, Isoniazid inhibit metabolism of carbamazepine
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  Oxcarbazepine • Newer congenerof carbamazepine • Toxic effects due to the epoxide metabolite are avoided • Drug interactions and auto induction of own metabolism are less marked, because it is a weak enzyme inducer • Risk of hepatotoxicity is estimated to be lower than carbamazepine; but that of hyponatremia is more • Indications are the same as for carbamazepine, but it may be better tolerated • Dose to dose it is 1½ times less potent
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  Eslicarbazepine • Prodrug • Rapidlyconverted in liver to the same active metabolite as is oxcarbazepine • Same range of therapeutic and toxic effects • Once daily dosing • Add-on drug for focal seizure with or without generalization only in adults
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  Valproic acid (Sodiumvalproate) • Valproate appears to act by multiple mechanisms: 1. A phenytoin-like frequency-dependent prolongation of Na+ channel inactivation. 2. Weak attenuation of Ca2+ mediated ‘T’ current (Ethosuximide like) 3. Augmentation of release of inhibitory transmitter GABA by inhibiting its degradation (by GABA- transaminase) 4. Blockade of excitatory NMDA type of glutamate receptor
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  Uses • Drug ofchoice for 1. Generalised tonic clonic seizures 2. Absence seizures 3. Myoclonic seizures 4. Atonic seizures • Alternative/adjuvant drug for focal seizures • Mania and bipolar illness  As alternative to Lithium
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  Adverse effects (VALPROATE) •Vomiting • Alopecia • Liver toxicity • Pancreatitis • Rash • Obesity • Agranulocytosis • Teratogenic (Neural tube defects in offspring)
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  • E (dEntist) Dentist may face excess bleeding while executing a dental procedure as Valproate causes increased bleeding tendency • E  Epigastric pain
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  Interactions 1. ↑ plasmalevels of Phenobarbitone and Lamotrigine 2. Displaces Phenytoin from protein binding site 3. Inhibits hydrolysis of active epoxide metabolite of Carbamazepine 4. Concurrent administration of Clonazepam and valproate is C/I (absence status may be pptd.) 5. Foetal abnormalities are more common if Valproate and Carbamazepine are given concurrently
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  Divalproex (Semisodium valproate) • Coordinationcompound of valproic acid with sodium valproate (1:1) • Oral absorption is slower, but bioavailability is the same • Gastric tolerance may be better • Primarily used in mania and bipolar illness • May be used like Valproate
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  Lamotrigine • Blocks voltagesensitive Na+ channels • Broad-spectrum antiepileptic • S/E  Sleepiness, dizziness, diplopia, ataxia and vomiting. Rash may be a severe reaction, particularly in children, requiring withdrawal • Dose of lamotrigine should be reduced to half in patients taking Valproate
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  Uses • Drug ofchoice for 1. Generalised tonic clonic seizures 2. Absence seizures 3. Myoclonic seizures 4. Atonic seizures 5. Focal seizures
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  Gabapentin • Enhances GABArelease, but does not act as agonist at GABAA receptor • Adjunctive therapy in focal seizures • 1st line drug for neuralgic pain due to diabetic neuropathy and postherpetic neuralgia • Prophylactic effect in migraine • Alternative drug for phobic states • S/E  Sedation, tiredness, dizziness, tremors & unsteadiness
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  Pregabalin • Similar togabapentin • Used for 1. Neuropathic pain (diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome (CRPS) 2. Chronic pain S/E  Poor concentration, rashes and allergic reactions have been complained
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  Levetiracetam • 1st linedrug  Focal seizures • 2nd line drug  GTCS and typical absence seizures • MOA  Binds selectively to a synaptic vesicular protein ‘SV2A’, and this may alter release of glutamate and/or GABA across the synapse, thereby exerting anti-seizure effect • S/E  Sleepiness, dizziness, weakness
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  Topiramate • 1st linedrug in atypical absence, myoclonic and atonic seizures • 2nd line drug in GTCS and focal seizures • Broad spectrum anticonvulsant drug acting by :- 1. Prolongation of Na+ channel inactivation 2. Suppression of repetitive neuronal firing 3. GABA potentiation 4. Antagonism of certain glutamate receptors 5. Neuronal hyperpolarization through K+ channels
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  • A/E Impairment of attention, sedation, ataxia, word finding difficulties, poor memory, weight loss, paresthesias and renal stones. • Other uses • Approved for prophylaxis of migraine (when β blockers/other prophylactics are C/I or ineffective)
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  Zonisamide • Adjunctive therapyin GTCS and focal seizures • MOA  Prolongation of Na+ channel inactivation • S/E  Somnolence, dizziness, headache, irritability and anorexia. • Metabolic acidosis and renal stones can occur. • C/I  In patients sensitive to Sulfonamides
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  Lacosamide • Adjunctive therapyin focal seizures • MOA  ↑ Na+ channel inactivation and suppresses repetitive firing of neurons • A/E  Ataxia, vertigo, diplopia, tremor, depression and cardiac arrhythmia
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  Treatment of epilepsies •Antiepileptic drugs suppress seizures, but do not cure the disorder • Aim  Control and prevent all seizure activity at an acceptable level of side effects • Cause of epilepsy should be searched; if found and treatable, an attempt to remove it should be made • Some general principles of symptomatic treatment with antiepileptic drugs are 
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  1. Start withone 1st line drug 2. Initiate treatment early 3. Start at a low dose; gradually ↑ until 1. Effective control of seizures is achieved OR 2. Side-effects develop 4. Optimise adherence (use minimum number of doses per day) 5. If 1st drug fails start second 1st line drug, followed if possible by gradual withdrawal of 1st 6. If 2nd drug fails, start 2nd line drug in combination with the preferred baseline drug at maximum tolerated dose (beware interactions)
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  7. If thiscombination fails, replace 2nd line drug with alternative second-line drug 8. If this combination fails, check adherence and reconsider diagnosis (Are events seizures? Occult lesion? Treatment adherence/alcohol/drugs confounding response?) 9. Consider alternative, non-drug treatments (e.g. epilepsy surgery, vagal nerve stimulation) 10. Use minimum number of drugs in combination at any one time
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  Epilepsy in pregnancy 1.Pre-conception counselling  Best; start folic acid (5 mg daily for 2 months) before conception to reduce the risk of fetal malformations. 2. Risk of fetal malformation is minimised if a single drug is used. Carbamazepine and Lamotrigine have the lowest incidence of major fetal malformations 3. Prophylactic folic acid supplementation in 2, 3 tri. 4. Vit. K in the last month of pregnancy
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  Dental implications 1. Dentistshave to recognize and manage Phenytoin induced gum hypertrophy 2. In an epileptic patient, dental procedure should be carried out only after ensuring that the patient is under adequate anticonvulsant drug cover and has taken his/her medication 3. In the event of a patient developing an attack of GTCS during dental procedure, the first priority is to prevent injuries due to biting or fall. Ensure that the patient is secure on the flat dental chair or floor
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  • Any dentureor instrument should be immediately removed from the mouth • The head should be turned to the side to prevent the tongue from falling back and obstructing the airway • Give oxygen through a face mask to support respiration if any sign of cyanosis is seen • Do not attempt to stop convulsive movements by restraining the patient • In case the seizures do not stop or recur within 10- 20 minutes, management is as for status epilepticus
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  Status epilepticus • Continuousseizures or repetitive, discrete seizures with impaired consciousness in the interictal period 1. GCSE (e.g., persistent, generalized electrographic seizures, coma, and tonic-clonic movements) 2. Nonconvulsive status epilepticus (e.g., persistent absence seizures or focal seizures with confusion or partially impaired consciousness, and minimal motor abnormalities) • Practical def.  Duration of seizures prompts the acute use of anticonvulsant therapy • In GCSE  When seizures last beyond 5 min.
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  Febrile convulsions • Somechildren (<5 yrs.) develop convulsions during fever • Attempt should be made to see that they do not develop fever, but when they do, temperature should not be allowed to rise by using paracetamol and external cooling • DOC  Rectal diazepam 0.5 mg/kg • In recurrent cases or those at particular risk of developing epilepsy  Intermittent prophylaxis with diazepam (oral or rectal)
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  Infantile spasms (hypsarrhythmia) •Therapy of this condition is unsatisfactory • antiepileptic drugs are generally useless • Corticosteroids afford symptomatic relief but cannot be used for long-term due to A/E • Clonazepam, Valproate and Vigabatrin may afford some relief