“Anti Epileptic Drugs II” PHARMACOLOGY Neuropsychiatry Block 2017/ 2018 Mrs. Sandra Hababeh

Learning objectives Describe types of epilepsy List the antiepileptic drugs Describe briefly the mechanism of action and rational of use of anti epileptic drugs Enumerate the clinical uses of each drug Describe treatment of status epilepticus اسم ورقم المقرر – Course Name and No. 6/23/2019

Newer Drugs اسم ورقم المقرر – Course Name and No. 6/23/2019

1. Gabapentin (Neurontin) Used as Adjunctive therapy in partial and generalized tonic- clonic seizures. Mechanism of action Decreased release of glutamate from presynaptic terminals (most likely due to blockade of presynaptic voltage-gated Ca++ channels) Increased brain GABA concentration Note: An Analog of GABA that does not act on GABA receptors, it may alter its metabolism, release and transport. Adverse effects: Somnolence, dizziness, ataxia, headache, tremor اسم ورقم المقرر – Course Name and No. 6/23/2019

2. Lamotrigine Used as Adjunctive therapy with valproate. Use: against generalized seizures. M.O.A: blocks sodium channels, as well as high voltage- dependent calcium channels. Adverse effects: Dizziness, Headache, Diplopia, Nausea, Somnolence, Life threatening rash “Stevens- Johnson” اسم ورقم المقرر – Course Name and No. 6/23/2019

3. Felbamate M.O.A: modulation of NMDA receptor (glutamate receptor) Because of its severe side effects, it has been relegated to a third-line drug used only for refractory cases. Adverse effects: aplastic anemia and severe hepatitis restricts its use. اسم ورقم المقرر – Course Name and No. 6/23/2019

4. Tiagabine Adjunctive therapy for partial seizures Interferes with GABA reuptake Adverse effects: CNS sedative اسم ورقم المقرر – Course Name and No. 6/23/2019

5. Zonisamide Mechanism of action: Likely multiple, including Blockade of Na+ channels Blockade of T type CA++ channels. Enhancement of GABAergic transmission Inhibition of glutamatergic transmission Adverse effects Drowsiness, dizziness, headache, irritability. Allergic reactions (it is a sulfonamide) Therapeutic uses: adjunctive therapy in : Partial and tonic clonic seizures. Myoclonic seizures اسم ورقم المقرر – Course Name and No. 6/23/2019

6. Topimerate M.O.A: blockade of Na+ channels, increases frequency of GABAA channel openings, may interfere with glutamate binding to AMPA/KA receptor Use: Effective as monotherapy for partial or generalized seizures. Adverse effects: CNS sedative اسم ورقم المقرر – Course Name and No. 6/23/2019

7. Levetiracetam It is approved for adjunct therapy of focal onset, myoclonic, and primary generalized tonic–clonic seizures in adults and children. The exact mechanism of anticonvulsant action is unknown. The drug is well absorbed orally and excreted in urine mostly unchanged, resulting in few to no drug interactions. اسم ورقم المقرر – Course Name and No. 6/23/2019

Inhibitory and stimulation mechanisms of AEDS اسم ورقم المقرر – Course Name and No. 6/23/2019

اسم ورقم المقرر – Course Name and No. 6/23/2019

Status Epilepticus In status epilepticus, two or more seizures occur without recovery of full consciousness in between episodes, it is called “status epilepticus”. Status epilepticus is life threatening and requires urgent hospital treatment. If untreated immediately by IV medications, it can lead to death due aspiration, hypotension, cardiac arrhythmia, renal or hepatic failure. اسم ورقم المقرر – Course Name and No. 6/23/2019

Management of Status Epilepticus Initial: Ensure airway is patent, give oxygen to prevent cerebral hypoxia Check pulse, Bp, glucose and respiratory rate. Secure intravenous access Send blood for: glucose, urea and electrolytes, calcium and magnesium, liver function, anti epileptic levels. If seizures last >5mins, diazepam 10mg IV (or rectally) or lorazepam 4mg IV, repeat once only after 15 min. Correct any metabolic trigger, e.g. hypoglycemia اسم ورقم المقرر – Course Name and No. 6/23/2019

Management of Status Epilepticus cnt’d Ongoing: If seizures continue > 30mins: IV infusion of ; Phenytoin , fosphenytoin (more expensive), or phenobarbital, with cardiac monitoring If seizures still continue after 30mins-60mins (refractory status): Transfer to ICU Intubation, Ventilation and general anesthesia with propofol or thiopental. EEG monitor اسم ورقم المقرر – Course Name and No. 6/23/2019

Management of Status Epilepticus cnt’d اسم ورقم المقرر – Course Name and No. 6/23/2019

Antiepeliptics and Pregnancy: Monotherapy usually better than drugs combination. All women considering pregnancy should be on high doses (1 to 5 mg) of folic acid prior to conception. If possible, women already taking valproate should be placed on other therapies prior to pregnancy (Lamotrigine) Phenytoin, sodium valproate are absolutely contraindicated in pregnancy اسم ورقم المقرر – Course Name and No. 6/23/2019

FDA Pregnancy Risk for Antiseizure Drugs

Treatment of Epilepsy: Drugs Vagal nerve stimulation Surgery Ketogenic diet

Vagal Nerve Stimulation اسم ورقم المقرر – Course Name and No. 6/23/2019

Summary Epilepsy is classified into partial or generalized according to the site of lesion. The exact mechanism of action of antiepileptics is not known. Phenytoin is mainly used for treatment of generalized tonic-clonic seizure Carbamazepine is mainly used for treatment of partial seizures

Summary ( con.) Sodium valproate is a broad spectrum antiepileptic drug. Lamotrigine & levetiracetam are used as monotherapy or adjunctive therapy in refractory cases. Lorazepam , diazepam , phenytoin are used intravenously for treatment of status epilepticus.

Recommended Reference: “Lippincott's Illustrated Reviews” “Davidson’s Principles & Practise of Medicine ”

Good luck  Mrs.Sandra Hababeh