1. دکتر محمد ربانی گروه فارماکولوژی rabbani@pharm.mui.ac.ir1

2.  Introduction Introduction  Classification of epilepsy Classification of epilepsy  Antiepileptic drugs Antiepileptic drugs  Barbituric Acid Derivatives Barbituric Acid Derivatives  Phenytoin, Mephenytoin & Ethotoin Phenytoin, Mephenytoin & Ethotoin  Ethosuximide Ethosuximide  Carbamazepine & Oxcarbazepine Carbamazepine & Oxcarbazepine  Benzodiazepines Benzodiazepines  Valproic Acid & Sodium Valproa Valproic Acid & Sodium Valproa  Gabapentin Gabapentin  Lamotrigine Lamotrigine  Felbamate Felbamate  Vigabatrin & Tiagabine VigabatrinTiagabine  Topiramate & Zonisamide Topiramate & Zonisamide  Withdrawal & Overdose Withdrawal & Overdose  Drug Pictures Drug Pictures

3.  Abnormal and excessive electrical discharges in a group of nerve cells affecting brain function  Abnormality in neuronal plasma membranes results in increased permeability and responsiveness to stimuli  Diagnosed by clinical signs and symptoms of seizure activity and by abnormal brain wave patterns on the EEG patterns on the EEG rabbani@pharm.mui.ac.ir 3

7.  1-2 % of the world's population has epilepsy, the second most common neurologic disorder after stroke.  Epilepsy is a chronic disorder characterized by recurrent seizures.  Seizures are finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons because of:  All neurologic diseases  Infection  Neoplasm  Head injury  Heredity

8.  Hypoglycemia, fever, electrolyte imbalances, overdoses of drugs, withdrawal of alcohol or sedative-hypnotic drugs or as a result of epilepsy  Cause is idiopathic in 60-80% of children  Seizures occur in a chronic, recurrent pattern rabbani@pharm.mui.ac.ir 8

9.  Partial seizures  Simple partial  Complex partial  Secondarily generalized  Generalized seizures  Generalized tonic-clonic (grand mal) Generalized tonic-clonic (grand mal) Generalized tonic-clonic (grand mal)  Absence (petit mal) Absence (petit mal) Absence (petit mal)  Tonic  Atonic  Clonic and myoclonic  Infantile spasms Minimal spread of the abnormal discharge Tonic rigidity of all extremities for 15-30 seconds. The clonic phase with massive jerking of the body slows over 60-120 seconds Clonic jerking of the eyelids or extremities and automatisms may occur. involves the limbic system with automatisms limbic systemlimbic system

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13.  Tonic-clonic. Tonic phase is sustained skeletal contraction, clonic phase is rapid and rhythmic jerking movements.  Absence—abrupt alterations in consciousness that last only seconds  Status Epilepticus—life-threatening, generalized tonic-clonic convulsions lasting for several minutes or at close intervals. Hypotension, hypoxia and cardiac dysrhythmias may occur. rabbani@pharm.mui.ac.ir 13

14. rabbani@pharm.mui.ac.ir 14 Antiepileptic drugs

15.  A drug which decreases the frequency and/or severity of seizures in people with epilepsy  Treats the symptom of seizures, not the underlying epileptic condition  Goal—maximize quality of life by minimizing seizures and adverse drug effects rabbani@pharm.mui.ac.ir 15

16.  Drugs act by one of the three mechanisms:three mechanisms  Enhancement of gabaergic (inhibitory) transmission  Diminution of excitatory (glutamatergic) transmission  Modification of ionic conductances (Na + or Ca 2+ )  Drugs used in partial & generalized tonic-clonic seizures are the same.  Refractory cases may respond to vagus-nerve stimulation (VNS) for partial seizures.

20. First effective antiseizure agent Mechanism:  GABA A receptor mediated  Continued use – sedation effect lost but not anticonvulsant action  Raises seizure threshold and limits spread Phenobarbital: Uses  Partial and generalized tonic-clonic seizures  Promotes sleep and sedation Drug of choice:  No longer drugs of choice – need monitoring  Can be used as 2 nd -line in all forms of epilepsy Adverse effects: D ependence, Nystagmus, Ataxia, CNS depression rabbani@pharm.mui.ac.ir

21.  The major action is to block sodium channels and inhibit the generation of rapidly repetitive action potentials.repetitive action potentials  Metabolism is dose-dependent with saturation kinetics.dose-dependent  Some drug precipitation after intramuscular injection occurs so IM route is not recommended.  It takes 7 days (at low blood levels) or 6 weeks (at higher levels) to reach steady-state after every dosage change.

22. Toxic Level

24.  Phenytoin induces microsomal enzymes.microsomal enzymes  Toxicity:  Nystagmus occurs early, but is not an indication for decreasing the dose.  Diplopia & ataxia (the most common adverse effects requiring dosage adjustment)  Gingival hyperplasia Gingival hyperplasia  Coarsening of facial features, HirsutismHirsutism  megaloblastic anaemia, osteomalacia

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28.  Decreases effect of oral contraceptives, warfarin, glucocorticoids  Phenytoin level can be increased if used with diazepam, isoniazid (tuberculosis drug), cimetidine, alcohol, valproic acid rabbani@pharm.mui.ac.ir 28

29.  Considered drug of choice for  tonic clonic seizures, partial seizures  Also used for  cardiac arrhythmias & trigeminal neuralgic rabbani@pharm.mui.ac.ir 29

30.  Are similar to phenytoin.  Ethotoin is recommended for patients hypersensitive to phenytoin.  The toxicity of ethotoin is generally less severe than phenytoin, but the drug is less effective.

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32.  Drug of choice for : Simple absence seizures  Also used for: Myoclonic, atypical absences, atonic  Adverse effects: GI upset, drowsiness, dizziness, ataxia, allergic reactions, drug-induced SLE  MOA: Blocks low threshold, “transient” (T-type) Ca channels in thalamic neurons rabbani@pharm.mui.ac.ir 32

33.  Blocks sodium channels  It is not sedative.  Is very effective in patients with trigeminal neuralgia.

34.  Considered a drug of choice for  tonic clonic seizures  partial seizures  trigeminal neuralgia  prophylaxis of manic depressive illness  Potent inducer of hepatic enzymes  own half life reduces over 2-3 weeks  increases metabolism of theophylline, warfarin..  complex drug interactions with other anticonvulsants rabbani@pharm.mui.ac.ir 34

35.  Diplopia & ataxia are the most common dose related adverse effects.  Idiosyncratic blood dyscrasias, including fatal cases of aplastic anemia and agranulocytosis.  Most have been in elderly patients with trigeminal neuralgia.  Most have occurred within the first 4 months of treatment.

36.  Is less potent than carbamazepine.  It may have an improved toxicity profile.  The drug appears to induce hepatic enzymes to a lesser extent than carbamazepine.

37.  Most too sedative for clinical use  Clonazepam and clobazam are used clinically  effectiveness wanes on long term therapy  Adverse effects: Sedation, Hypotonia, impaired co-ordination rabbani@pharm.mui.ac.ir 37

38.  Seizures associated with Lennox-Gastaut syndrome (a severe form of epilepsy)  Akinetic seizures (known as atonic seizures), characterized by a sudden loss of muscle tone, causing "drop attacks"  Myoclonic seizures (brief muscle jerks)  Absence seizures, characterized by brief periods of decreased awareness or "spacing out."

39.  Drug of choice if the patient has concomitant absence seizures & generalized tonic-clonic attacks.  The most common adverse effects are nausea, vomiting and abdominal pain.  A pregnant woman taking valproate has a 1-2% risk of having a child with spina bifida.  The idiosyncratic toxicity is hepatotoxicity  More than 50 fatalities in the USA alone  The risk is greatest under the age of 2 years  Most fatalities within 4 months after therapy Although it is important to minimize exposure to antiseizure drugs, it is also important not to allow maternal seizures to go unchecked.

40.  MOA:  May enhance GABA transmission  Blocks voltage-dependent Na channels  Does not induce drug metabolism  Adverse effects  Thinning and curling of hair in 10%  Rare hepatic and pancreatic disorders  Coagulopathy (inhibition of platelet aggregation)  Increased appetite and weight gain rabbani@pharm.mui.ac.ir 40

41.  Gabapentin is an analog of GABA which is effective against partial seizures.  In spite of its structural resemblance to GABA, gabapentin does not act directly on GABA receptors.  Gabapentin increases GABA concentration in the brain.  Gabapentin is effective as an adjunct against partial seizures and generalized tonic-clonic seizures.

42.  Widely used to relieve pain, especially neuropathic pain.  Well tolerated in most patients  With mild side-effect profile, and passes through the body unmetabolized. rabbani@pharm.mui.ac.ir 42

43.  Suppresses sodium and Ca 2+ channels and decreases the release of glutamate.  Lamotrigine is effective as monotherapy for partial seizures, and is widely prescribed for this indication. Primary and secondary tonic- clonic seizures, bipolar disorder.  A potentially life-threatening dermatitis will develop in 1-2% of pediatric patients.

44.  Not a first line antiepileptic drug  Only in patients who respond inadequately to alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed acceptable. MOA: Unknown rabbani@pharm.mui.ac.ir 44

45.  An analogue of GABA.  It is irreversible inhibitor of 4-aminobutyrate transaminase  It is used as an adjunctive treatment in treatment resistant epilepsy, complex partial seizures, secondary generalized seizures rabbani@pharm.mui.ac.ir 45

46.  It is used as an adjunctive treatment for partial seizures in ages 12 and up.  It is also used in the treatment for panic disorder, anxiety disorders and neuropathic pain rabbani@pharm.mui.ac.ir 46 A selective GABA reuptake inhibitor.

47.  Used for the treatment and control of partial seizures and severe tonic-clonic (grand mal) seizures and also for the prevention of migraine headaches.  In children it is also used for treatment of Lennox-Gastaut syndrome. rabbani@pharm.mui.ac.ir 47

48.  It blocks sodium channels. It ihibits carbonic anydrase. It also affects GABA and Glutamate receptors  Acute myopia and glaucoma may require prompt drug withdrawal.

49.  Blocks voltage-dependent Na channels at high firing frequencies  Increases frequency at which GABA opens Cl- channels (different site than benzodiazepines)  Antagonizes glutamate action at AMPA/kainate receptor subtype rabbani@pharm.mui.ac.ir 49

50.  for treatment of grand mal and partial seizures in adults and children  Can also be prescribed off-label to treat certain types of tremors.  Works by preventing abnormal electrical activity from starting and spreading to other parts of the brain.

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93. rabbani@pharm.mui.ac.ir93 Inducers Inhibitors phenobarbitalerythromycin primidonenifedipine/verapamil phenytointrimethoprim/sulfa carbamazepinepropoxyphene tobacco/cigarettescimetidine valproate

94.  Substrates (metabolism enhanced by inducers): steroid hormones theophylline tricyclic antidepressants vitamins warfarin (many more) P-Slide 94

95.  Inducers: Increase clearance and decrease steady-state concentrations of other substrates  Inhibitors: Decrease clearance and increase steady-state concentrations of other substrates rabbani@pharm.mui.ac.ir 95

96.  Partial Seizures (simple partial, complex partial, or secondary generalized)- Valproic acid, Carbamazepine, Phenytoin  Generalized Seizures- Valproic acid (Tonic- clonic; grand mal), Ethosuximide (Absence; petit mal) rabbani@pharm.mui.ac.ir 96

97.  1857 - Bromides  1912 - Phenobarbital  1937 - Phenytoin  1954 - Primidone  1960 - Ethosuximide  1974 - Carbamazepine  1975 - Clonazepam  1978 - Valproate rabbani@pharm.mui.ac.ir 97

98.  1993 - Felbamate, Gabapentin  1995 - Lamotrigine  1997 - Topiramate, Tiagabine  1999 - Levetiracetam  2000 - Oxcarbazepine, Zonisamide rabbani@pharm.mui.ac.ir 98

99. Initiation of therapy  Aim for monotherapy (efficacious and safe)  Start with low dose - escalate over about a month  Should control 80% of patients on one agent  If unable to achieve control  change to new agent of different class OR add a second agent of a different class  About 3 months treatment required to determine efficacy rabbani@pharm.mui.ac.ir 99

100. The Sodium Channel: A. Resting State B. Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in. C. Refractory State, Inactivation – reduce the rate of recovery. Na + Sustain channel in this conformation Anticonvulsant mechanism – contd. m gate h gate