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Antiseizure drugs

Antiseizure drugs. Dr M Mosaddegh. Overview. Seizures are sudden episodes of neurological dysfunction caused by abnormal electrical activity of the brain Seizures are common 1% of the population will have a seizure . Epilepsy.

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Antiseizure drugs

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  1. Antiseizure drugs Dr M Mosaddegh

  2. Overview • Seizures are sudden episodes of neurological dysfunction caused by abnormal electrical activity of the brain • Seizures are common • 1% of the population will have a seizure

  3. Epilepsy A group of chronic CNS disorders characterized by recurrent seizures. • Seizures are sudden, transitory, and uncontrolled episodes of brain dysfunction resulting from abnormal discharge of neuronal cells with associated motor, sensory or behavioral changes.

  4. Causes for Acute Seizures • Brain Trauma • Encephalitis • Drugs • PKU • Photo epilepsy • Birth trauma • Withdrawal from depressants • Tumor • Hypoxia • Idiopathic • High fever(Febrile convulsion) • Hypoglycemia • Extreme acidosis • Extreme alkalosis • Hyponatremia • Hypocalcemia • Infection e.g. meningitis, brain abscess, viral encephalitis

  5. Classification of Epileptic Seizures I. Partial (focal) Seizures • Simple Partial Seizures • Complex Partial Seizures II. Generalized Seizures • Generalized Tonic-Clonic Seizures • Absence Seizures • Tonic Seizures • Atonic Seizures • Clonic and Myoclonic Seizures F. Infantile Spasms

  6. AED Response – Established AEDs • Earlier studies suggested that many patients respond to monotherapy but fewer and fewer patients respond to combination therapy. 70% controlled* Monotherapy 30% controlled* on 2 drugs 30% poorly managed • Combinations of two or more drugs provide little more benefit * Controlled was defined as adequately managed but not necessarily seizure-free

  7. I. Partial (Focal) Seizures Simple Partial Seizures Complex Partial Seizures

  8. Scheme of Seizure Spread Simple (Focal) Partial Seizures Contralateral spread

  9. I. Partial (Focal) Seizures A. Simple Partial Seizures (Jacksonian) • Involves one side of the brain at onset. • Focal w/motor, sensory or speech disturbances. • Confined to a single limb or muscle group. • Seizure-symptoms don’t change during seizure. • No alteration of consciousness. EEG: Excessive synchronized discharge by a small group of neurons. Contralateral discharge.

  10. Scheme of Seizure Spread Complex Partial Seizures Complex Secondarily Generalized Partial Seizures

  11. I. Partial (focal) Seizures B. Complex Partial Seizures(Temporal Lobe epilepsy or Psychomotor Seizures) • Produces confusion and inappropriate or dazed behavior. • Motor activity appears as non-reflex actions. Automatisms (repetitive coordinated movements). • Wide variety of clinical manifestations. • Consciousness is impaired or lost. EEG: Bizarre generalized EEG activity with evidence of anterior temporal lobe focal abnormalities. Bilateral.

  12. II. Generalized Seizures In Generalized seizures, both hemispheres are widely involved from the outset. Manifestations of the seizure are determined by the cortical site at which the seizure arises. Present in 40% of all epileptic Syndromes.

  13. II. Generalized Seizures (con’t) • Generalized Tonic-Clonic Seizures Recruitment of neurons throughout the cerebrum Major convulsions, usually with two phases: 1) Tonic phase 2) Clonic phase Convulsions: motor manifestations, may or may not be present during seizures, excessive neuronal discharge. Convulsions appear in Simple Partial and Complex Partial Seizures if the focal neuronal discharge includes motor centers; they occur in all Generalized Tonic-Clonic Seizures regardless of the site of origin. Atonic, Akinetic, Absence Seizures are non-convulsive

  14. II. Generalized Seizures (con’t) A. Generalized Tonic-Clonic Seizures Tonic phase: - Sustained powerful muscle contraction (involving all body musculature) which arrests ventilation. EEG: Rythmic high frequency, high voltage discharges with cortical neurons undergoing sustained depolarization, with protracted trains of action potentials.

  15. II. Generalized Seizures (con’t) A. Generalized Tonic-Clonic Seizures Clonic phase: - Alternating contraction and relaxation, causing a reciprocating movement which could be bilaterally symmetrical or “running” movements. EEG: Characterized by groups of spikes on the EEG and periodic neuronal depolarizations with clusters of action potentials.

  16. Scheme of Seizure Spread Generalized Tonic-Clonic Seizures Both hemispheres are involved from outset

  17. Neuronal Correlates of Paroxysmal Discharges Generalized Seizures

  18. Neuronal Correlates of Paroxysmal Discharges

  19. II. Generalized Seizures B. Absence Seizures (Petite Mal) • Brief and abrupt loss of consciousness. • Sometimes with no motor manifestations. • Usually symmetrical clonic motor activity varying from occasional eyelid flutter to jerking of the entire body. • Typical 2.5 – 3.5 Hz spike-and-wave discharge. • Usually of short duration (5-10 sec), but may occur dozens of times a day.

  20. II. Generalized Seizures B. Absence Seizures (Petite Mal) (con’t) • Often begin during childhood (daydreaming attitude, no participation, lack of concentration). • A low threshold Ca2+ current has been found to govern oscillatory responses in thalamic neurons (pacemaker) and it is probably involve in the generation of these types of seizures. EEG: Bilaterally synchronous, high voltage 3-per-second spike-and-wave discharge pattern. spike phase: neurons generate short duration depolarization and a burst of action potentials. No sustained depolarization or repetitive firing.

  21. Scheme of Seizure Spread Primary Generalized Absence Seizures Thalamocortial relays are believed to act on a hyperexcitable cortex

  22. Neuronal Correlates of Paroxysmal Discharges Generalized Absence Seizures

  23. Scheme of Seizure Spread

  24. II. Generalized Seizures (con’t) C. Tonic Seizures • Opisthotonus, loss of consciousness. • Marked autonomic manifestations D. Atonic Seizures (atypical) • Loss of postural tone, with sagging of the head or falling. • May loose consciousness.

  25. II. Generalized Seizures (con’t) E. Clonic and Myoclonic Seizures • Clonic Seizures: Rhythmic clonic contractions of all muscles, loss of consciousness, and marked autonomic manifestations. • Myoclonic Seizures:Isolated clonic jerks associated with brief bursts of multiple spikes in the EEG. F. Infantile Spasms • An epileptic syndrome. • Attacks, although fragmentary, are often bilateral. • Characterized by brief recurrent myoclonic jerks of the body with sudden flexion or extension of the body and limbs.

  26. Types of s (focal) Primary

  27. Treatment of Seizures Goals: • Block repetitive neuronal firing. • Block synchronization of neuronal discharges. • Block propagation of seizure. Minimize side effects with the simplest drug regimen. MONOTHERAPY IS RECOMMENDED IN MOST CASES

  28. Treatment of Seizures Strategies: • Modification of ion conductances. • Increase inhibitory (GABAergic) transmission. • Decrease excitatory (glutamatergic) activity.

  29. Actions of Phenytoin on Na+ Channels Na+ • Resting State • Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in. • Refractory State, Inactivation Na+ Na+ Sustain channel in this conformation

  30. GABAergic SYNAPSE Drugs that Act at the GABAergic Synapse • GABA agonists • GABA antagonists • Barbiturates • Benzodiazepines • GABA synthesizing enzymes • GABA uptake inhibitors • GABA metabolizing enzymes GABA-T GAD GAT

  31. GLUTAMATERGIC SYNAPSE • Excitatory Synapse. • Permeable to Na+, Ca2+ and K+. • Magnesium ions block channel in resting state. • Glycine (GLY) binding enhances the ability of GLU or NMDA to open the channel. • Agonists: NMDA, AMPA, Kianate. Na+ Ca2+ AGONISTS GLU GLY Mg++ K+

  32. Chemical Structure of Classical Antiseizure Agents X may vary as follows: Barbiturates - C – N - Hydantoins - N – Oxazolidinediones – O – Succinimides – C – Acetylureas - NH2 –* *(N connected to C2) Small changes can alter clinical activity and site of action. e.g. At R1, a phenyl group (phenytoin) confers activity against partial seizures, but an alkyl group (ethosuximide) confers activity against generalized absence seizures.

  33. “Older” AEDs • Phenobarbital 1912 • Phenytoin 1938 • Primidone 1952 • Ethosuximide 1960 • Carbamazepine 1974 • Valproate 1978

  34. Newer AEDS • felbamate 1993 • gabapentin 1994 • lamotrigine 1995 • topiramate 1996 • tiagabine 1998 • levetiracetam 1999 • oxcarbazepine 2000 • Zonisamide 2000 • pregabalin 2005

  35. Treatment of Seizures • Hydantoins: phenytoin • Barbiturates: phenobarbital • Oxazolidinediones: trimethadione • Succinimides: ethosuximide • Acetylureas: phenacemide • Other: carbamazepine, lamotrigine, vigabatrin, etc. • Diet • Surgery, Vagus Nerve Stimulation (VNS).

  36. Treatment of Seizures • Most classical antiepileptic drugs exhibit similar pharmacokinetic properties. • Good absorption (although most are sparingly soluble). • Low plasma protein binding (except for phenytoin, BDZs, valproate, and tiagabine). • Conversion to active metabolites (carbamazepine, primidone, fosphenytoin). • Cleared by the liver but with low extraction ratios. • Distributed in total body water. • Plasma clearance is slow. • At high concentrations phenytoin exhibits zero order kinetics.

  37. Treatment of Seizures Structurally dissimilar drugs: • Carbamazepine • Valproic acid • BDZs. New compounds: • Felbamate • Gabapentin • Lamotrigine • Tiagabine • Topiramate • Vigabatrin

  38. Pharmacokinetic Parameters

  39. TREATMENT OF SEIZURES

  40. Treatament cont,d

  41. Treatment: • Up to 80% of patients can expect partial or complete control of seizures with appropriate treatment. • Antiepileptic drugs suppress but do not cure seizures • Antiepileptics are indicated when there is two or more seizures occurred in short interval (6m -1 y) • An initial therapeutic aim is to use only one drug (monotherapy)

  42. Treatment ( Cont. ) • Advantage of monotherapy: • fewer side effects, decreased drug-drug interactions, better compliance, lower costs • Addition of a second drug is likely to result in significant improvement in only approx. 10 % of patients.

  43. Treatment ( Cont. ) • when a total daily dose is increased, sufficient time (about 5 t 1l2) should be allowed for the serum drug level to reach a new steady-state level. • The drugs are usually administered orally • The monitoring of plasma drug levels is very useful • Precipitating or aggravating factors can affect seizure control by drugs

  44. Treatment ( Cont. ) • The sudden withdrawal of drugs should be avoided withdrawal may be considered after seizure- free period of 2-3 or more years • Relapse rate when antiepileptics are withdrawn is 20 -40 %

  45. When to Withdraw Antiepileptic Drugs? Normal neurological examination Normal IQ Normal EEG prior to withdrawal Seizure- free for 2-5 yrs or longer NO juvenile myoclonic epilepsy Patients not meeting this ideal profile in all points, withdrawal may be encouraged after careful assessement of the individual patient.

  46. The Cytochrome P-450 Enzyme System InducersInhibitors phenobarbital valproate primidone topiramate (CYP2C19) phenytoin oxcarbazepine(CYP2C19) carbamazepine felbamate (CYP2C19) felbamate (CYP3A) (increase phenytoin, topiramate (CYP3A)phenobarbital) oxcarbazepine (CYP3A)

  47. Phenytoin Pharmacokinetics • Well absorbed when given orally, however, it is also available as iv. (for emergency) • 80-90% protein bound • Induces liver enzymes (Very Important) • Metabolized by the liver to inactive metabolite • Metabolism shows saturation kinetics and hence t ½ increases as the dose increased • Excreted in urine as glucuronide conjugate • Plasma t ½ approx. 20 hours • Therapeutic plasma concentration 10-20 µg/ml (narrow) • Dose 300-400 mg/day

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