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Seizures and epilepsy FOR clinical pharmacy student

  1. By Dr. Hussein Abdeldayem, MD Professor of Pediatric Neurology Unit Faculty of medicine, Alex University FOR CLINICAL PHARMACY STUDENTS Childhood Seizures and epilepsy AED
  2. Seizures • Seizure /epilepsy in children is one of the most anxiety-provoking conditions for parents and a common reason for emergency department visits
  3. Seizure ? 1/10 Epilepsy ? 1/100
  4. Seizure  : the involuntary clinical manifestation (S &/or S) due to an abnormal and excessive excitation and synchronization of a population of cortical neurons 
  5. Seizure is anSeizure is an ACUTEACUTE ManifestationManifestation Epilepsy is aEpilepsy is a ChronicChronic DISEASEDISEASE
  6. Stay calm and manage effectively Handling of the active seizure
  7. Never restrain the child or place anything in the mouth
  8. Treatment • ABCDs • Specific treatment*
  9. ABCDs • Airway • Breathing • Circulation • Drugs *Initial studies include glucose, serum chemistries (most importantly sodium, magnesium, calcium, phosphate, BUN), arterial blood gas, AED levels (if applicable), CBC
  10. Lorazepam (ativan) 0.1 mg/kg Diazepam 0.3 mg/kg* PR diazepam 0.5 mg/kg
  11. • The clinical efficacy of benzodiazepines for management of seizure clusters is due to their ability to bind with high affinity to which of the following types of receptor sites? • Dopaminergic 2 • γ-aminobutyric acid A (GABAA) • Nicotinic acetylcholine • Sphingosine-1 phosphate
  12. Rectal Diazepam* • The absorption of oral diazepam is slow (1-2 hours) and variable. • Intramuscular diazepam has similar absorption problems, is painful and may cause muscle necrosis. • Suppositories have slow and variable absorption rates and are not recommended in an emergency. Rectal administration of the intravenous form of diazepam
  13. Rectal Diazepam* • Intravenous and rectal diazepam both stop seizures in more than 80% of cases within 10-15 minutes Less Resp Depression Less BP Depression Less CNS Depression Prolonged action
  14. Rectal Diazepam • Use IV ampoules (10mg/2ml) or gel • Use Insulin syringes* • Rectal administration (use lubricant) Dose: 0.5 MG/KG max: 10 mg Lubrication Diazepam adsorbs to plastic and thus needs to be stored in glass
  15. 3
  17. Mechanisms of Seizures • Defective balance between excitatory and inhibitory neurotransmission +VE -VE + -
  18. What causes neuronal hyperexcitability? • Changes in Excitatory receptors Excitatory amino acid receptors Enhancement: NMDA, AMPA • Excitatory AA : Glutamate, aspartate +VE
  19. What causes neuronal hyperexcitability? • Changes in Inhibitory receptors GABA – A receptors • inhibitory AA : GABA -VE Changes in ion channels Plus
  20. Epilepsy
  21. Number ??? Time onset?? ? FC, ? tetany More than oneMore than one More than one day apart More than one day apart unprovocativeunprovocative EPILEPSY
  22. EPILEPSY Aetiology • Idiopathic • Symptomatic (Acquired) • cryptogenic • Genetic • Structural (acquired)* • Unknown * More in neonates and infancts 1985 2010
  23. Classification according to EEG findings GeneralizedGeneralized FocalFocal Both Cerebral Hemispheres Only a part of a hemisphere Loss of Consciousness No loss of consciousness Treated by Valproate Treated by Carbamazipine MRIMRI Focal withFocal with 2ry G2ry G
  24. Pediatric Seizures Seizure Type Classification 3- Clinically (ILAE 1981)  GENERALIZED 1- Involves both cerebral hemispheres 2- Loss consciousness 2- EEG: generalized 3- no aura  FOCAL (PARTIAL) 1- involve one hemisphere 2- NO Loss of consciousness 3- EEG: focal activity 4- ± aura Partial (focal) with secondary generalization Partial (focal) with secondary generalization ± MRI ASKMRIASKMRI
  25. Myoclonic Atonic Mixed Absence Tonic Clonic Tonic-clonic Generalized SeizuresGeneralized Seizures Valproate clonazepam
  26. (focal)(focal) simplesimple MotorMotor Which type of seizure is this ?
  27. ComplexSimple Partial (Focal) Seizures 2ry Generalization Carbamazepine
  28. Practical points  Stop attacks with no S/EStop attacks with no S/E  Start with minimal doseStart with minimal dose duration : 2years from last attackduration : 2years from last attack  withdraw slowly for 3 monthswithdraw slowly for 3 months  DON’T CHANGE COOKERDON’T CHANGE COOKER TreatmentTreatment
  29. Practical Points DURATION OF TREATMENT 2 years from last attack Withdraw over 3 months
  30. 35 Would u treat first seizure? • In children , we can wait for second attack for epilepsy diagnosis (chronicity)
  31. (Valproate) • 20 – 60 mg/kg/d • Twice* • Forms Oral with dropper Oral with spoon 200 mg tablets 500 mg chrono tablets • Follow up of: Serum drug level (peak) Serum drug level (trough) SGOT, SGPT, PT
  32. (Carbamazepine) • 10 – 20 mg/kg/d* • Twice • Forms Oral (100 mg/5ml) 200 mg tablets 200 mg CR tablets 400 mg CR tablets • Follow up of: Serum drug level (peak) Serum drug level (trough) Blood CBC
  33. Levetiracetam • Dose • Children: weight/10 ml twice • Therapeutic plasma concentration • Not relevant • Indicated for ALL • Common side effects • Nausea, drowsiness, anorexia, headache, rash, • Very rarely leucopenia • Comments • No drug interactions described
  34. • 20 – 60 mg/kg/d • Twice • Forms: Oral: (100mg/1ml) 500 mg tablets • Blood Follow up: NONE • Onset of action • Add on, no drug interaction * Not before 4 years age (Levetiracetam)
  35. • Quick onset of action • No cognitive S/E • Bind specific CNS areas only as hippocampus • Not liver metabolism, not protein binding so not interact with other AED The starting dose of 20mg/kg/day was increased at intervals of 1 week by 10mg/kg/day, if necessary, up to a maximum dose of 60mg/kg/day. Steady state: 8hX5
  36. FDA approval for levetiracetam in infants and children from one month of age with partial onset seizures January 26, 2012
  37. Levetiracetam LEV is effective against post-stroke seizures LEV IS EFFECTIVE IN SE Brain Dev. 2010 Jul 12. Levetiracetam in brain ischemia: Clinical implications in neuroprotection and prevention of post-stroke epilepsy.
  38. • 10 – 20 mg/kg/d* • Twice • Forms Oral (100 mg/5ml) 200 mg tablets 200 mg CR tablets 400 mg CR tablets • Follow up of: Serum drug level (peak) Serum drug level (trough) Blood CBC • 20 – 60 mg/kg/d • Twice • Forms: Oral: (100mg/1ml) 250 mg tablets 500 mg tablets • Follow up: NONE * Not before 4 years age • 20 – 60 mg/kg/d • Twice* • Forms Oral with dropper Oral with spoon 200 mg tablets 500 mg chrono tablets • Follow up of: Serum drug level (peak) Serum drug level (trough) SGOT, SGPT, PT (Valproate) ( Carbamazepine) (Levetiracetam)
  39. 44 Why don’t patients comply? • Poor communication or information • Poor understanding of instructions • Cost • Side effects + • Poor dose regimes + • Difficult to swallow/nasty taste medication + Good information makes medicines work
  40. 45 AEDs • First-generation AEDs include phenobarbitone, phenytoin, carbamazepine, valproic acid clonazepam, and primidone • Since early 1990’s: lamotrigine, gabapentin, oxcarbazepine, levetiracetam, divalproex sodium, topiramate, zonisamide, vigabatrin, tiagabine, and felbamate • The latest AEDs to become available are pregabalin, lacosimide, and rufinimide.
  41. 46 Drugs that cause seizures • Chemotherapeutic agents: intrathecal MTX, L-aspariginase, chlorambucil • Immunosuppressants: cyclosporinA • Anti-infective agents: high dose penicillins, metronidazole • Antipsychotic/AD: phenothiazines, tricyclic antidepressant • Sympathomimetic as in cold therapy and antitussive drugs • Theophylline
  42. 47 Principles of drug usage • Monotherapy • Least dosage • First choice • Compliance: cost, dosage division, formula • Least S/E especially cognitive functions
  43. 48 AE S/E 5+1 • CNS S/E: drowsiness, irritability, headache, ataxia, tremors • GIT S/E: anorexia, abdominal pain, increase or decrease appetite • Dermal S/E; urticarial up to Steven Johnson syndrome and anaphylaxis • BM S/E: suppression (WBC,RBC, Platelets) • Teratogenic : especially valproate (neural tube defect) • + specific S/E •
  44. 49 VPA Specific S/E • Hepatitis • pancreatitis • Hyperammonia • INCREASE APPETITE AND OBESITY • Coagulation defect • Renal: proteinuria • Polycystic ovary
  45. 50 CARBAMAZEPINE S/E • Skin rash : allergy up to Steven Johnson
  46. 51 CLONAZEPAM S/E • Hyperkinesia, inattention • INSOMNIA • NERVOUSNESS
  47. 52 Phenobarbitone specific S/E • Hyperkinesia • Insomnia • Learning disorder
  48. 53 Phenytoin Specific S/E • Gum hyperplasia • Hirsuitism So not prefer in girls • Learning disorder • arrythmia
  49. 54 Phenytoin and GINGIVAL HYPERPLASIA • Etiology: ? (fibroblasts ↑ in CT) • Any age ( > in younger) • Male=female • Not depend in dosage • Strong correlation with dental hygiene • Usually between 2-18 months
  50. 55 Phenytoin and GINGIVAL HYPERPLASIA • EFFECT of Tissue overgrowth 1- delayed eruption 2-misalignment 3- retention of food and halitosis 4- disfigurement Treatment 1- dental hygiene 2- night gingival +ve pressure appliance 3- gingivectomy
  51. 56 Lamotregene Specific S/E • Skin rash especially with VPA • Irritability and insomnia (stimulant) • No cognitive S/E
  52. Thank youThank you

Editor's Notes

  1. Children with  seizures are often referred to the  emergency department where they are typically evaluated by a physician with limited knowledge of pediatric epileptology and undergo a costly and extensive work-up that contributes little to the final decision
  2. 1 in every 10 persons will experience a seizure at some time in their lifetime. 1 in every 100 persons will experience epilepsy resulting from excessive and abnormal discharge of cortical neurons
  3. Keep calm and Reassure care giver
  4. 1- lateral position and raise legs 2-Loosen clothing around neck and body 3- Ensure area around child is clear and safe
  5. * > 5 min
  6. 50 ml G50% B6 for infancy S spine Toxicology study ( blood and urine)
  7. Lorazepam longer action and less resp depression 4mg/1ml Midazolam : IV, IM , intranasal, buccal, rectal DZP ; Iv, rectal (gel of solution and not suppositories) / diastat (rectal gel) not suppository diazepam acts to suppress seizures through an interaction with (gamma)-aminobutyric acid (GABA) receptors of the A-type (GABA A )
  8. *use DZP gel (diastat) or IV solution Indication 1- severe epilepsy 2- with clusters (serial) seizures 3- prolonged seizures >5mg
  9. Diazepam given rectally appears to be as effective as intravenous diazepam in terminating seizures. It may have advantages, including more prolonged action (20-30 minutes compared to 10-20 minutes), Time to peak plasma levels after rectal administration (about 5-10 minutes) is longer than after intravenous injection (1-3 minutes). This time difference may be important in status epilepticus where rapid seizure termination is necessary. It also possibly explains the lower incidence of respiratory depression experienced with rectal administration. The prolonged action after rectal administration may prevent seizure recurrence and allow more time to seek medical assistance.
  10. Diazepam gel (diastat) or The breaking of ampoules (10 mg/2 mL) and the use of needles by non-medical carers can be difficult and dangerous. If it is necessary to dilute diazepam, it is important to dilute it correctly as certain volumes of normal saline or dextrose can result in the precipitation of diazepam. Some institutions like the Royal Children's Hospital in Melbourne prepare 25 mL bottles of a rectal solution (1 mg/mL) using 50% propylene glycol in water. This is easy to use and does not expire for one year.3 Diazepam adsorbs to plastic and thus needs to be stored in glass. There are anecdotal reports of using diazepam oral mixture rectally, but its efficacy is not proven and thus cannot be recommended. Oil in water emulsions of injectable diazepam (e.g. Diazemuls) are slowly absorbed rectally and thus are inappropriate to use. A lubricated and suitably soft rectal tube is necessary as there are reports of hard plastic nozzles damaging the rectum. It is recommended that the tube or syringe is introduced only 4-5 cm into the rectum. Theoretically, administration of drugs higher into the rectum may result in greater first-pass metabolism, but clinically this is of minimal importance with rectal diazepam.
  11. If possible, infants and toddlers should be placed prone for rectal diazepam to be administered. Older children should be positioned on their side, in the recovery position. After administration, keep the child in the same position and hold the buttocks together for a few minutes to limit leakage from the rectum.
  12. NMDA receptors: Sustains long-lasting depolarization events
  13. There are two classes of GABA receptors: GABA-A and GABA-B. GABA – A Stimulation: Activation leads to membrane hyperpolarization via inflow of Cl and outflow K Decreased neuronal firing
  14. 1 in every 10 persons will experience a seizure at some time in their lifetime. 1 in every 100 persons will experience epilepsy resulting from excessive and abnormal discharge of cortical neurons
  15. Aim : to stop attacks No attacks / No S/E Start with minimal dose and increase gradually Stop if side effects appeared Don’t withdraw AED suddenly but gradually Do not change cooker
  16. After 48 hrs , LVT will start main effect. Levetiracetam is one of the agents that has a short half-life, has a half-life of about 7- 8 hours; but its pharmacodynamic action may extend considerably beyond that. If an agent has a short half-life, it only takes 5 half-lives to reach a steady state
  17. Keppra® was previously approved in the U.S. as adjunctive therapy for partial onset seizures in adults and children four years of age and older with epilepsy.
  18. levetiracetam is both safe and effective against post-stroke seizures due to the potential neuroprotective role in brain ischemia