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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 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. 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 Classification of Epileptic Seizures I. Partial (focal) Seizures A. Simple Partial Seizures B. Complex Partial Seizures II. Generalized Seizures A. Generalized Tonic-Clonic Seizures B. Absence Seizures C. Tonic Seizures D. Atonic Seizures E. Clonic and Myoclonic Seizures F. Infantile Spasms 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 9 I. Partial (Focal) Seizures A. Simple Partial Seizures B. Complex Partial Seizures Scheme of Seizure Spread Simple (Focal) Partial Seizures Contralateral spread 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. Scheme of Seizure Spread Complex Partial Seizures Complex Secondarily Generalized Partial Seizures 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. 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. II. Generalized Seizures (con’t) A. 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 nonconvulsive 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. 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. Scheme of Seizure Spread Generalized Tonic-Clonic Seizures Both hemispheres are involved from outset Neuronal Correlates of Paroxysmal Discharges Generalized Seizures Neuronal Correlates of Paroxysmal Discharges 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. 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-andwave discharge pattern. spike phase: neurons generate short duration depolarization and a burst of action potentials. No sustained depolarization or repetitive firing. Scheme of Seizure Spread Primary Generalized Absence Seizures Thalamocortial relays are believed to act on a hyperexcitable cortex Neuronal Correlates of Paroxysmal Discharges Generalized Absence Seizures Scheme of Seizure Spread 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. • E. • • II. Generalized Seizures (con’t) 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. Types of s (focal) Primary 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 Treatment of Seizures Strategies: • Modification of ion conductances. • Increase inhibitory (GABAergic) transmission. • Decrease excitatory (glutamatergic) activity. Actions of Phenytoin on Na+ Channels Na+ A. Resting State B. Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in. Na+ Na+ C. Refractory State, Inactivation Sustain channel in this conformation GABAergic SYNAPSE Drugs that Act at the GABAergic Synapse GABA-T GAD GAT • • • • • GABA agonists GABA antagonists Barbiturates Benzodiazepines GABA synthesizing enzymes • GABA uptake inhibitors • GABA metabolizing enzymes GLUTAMATERGIC SYNAPSE Na+ Ca2+ AGONISTS GLU GLY Mg++ K+ • 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. Chemical Structure of Classical Antiseizure Agents X may vary as follows: Barbiturates -C–NHydantoins -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. “Older” AEDs • • • • • • Phenobarbital Phenytoin Primidone Ethosuximide Carbamazepine Valproate 1912 1938 1952 1960 1974 1978 Newer AEDS • • • • • • • • • felbamate gabapentin lamotrigine topiramate tiagabine levetiracetam oxcarbazepine Zonisamide pregabalin 1993 1994 1995 1996 1998 1999 2000 2000 2005 Treatment of Seizures 1) 2) 3) 4) 5) 6) Hydantoins: phenytoin Barbiturates: phenobarbital Oxazolidinediones: trimethadione Succinimides: ethosuximide Acetylureas: phenacemide Other: carbamazepine, lamotrigine, vigabatrin, etc. 7) Diet 8) Surgery, Vagus Nerve Stimulation (VNS). 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. Treatment of Seizures Structurally dissimilar drugs: • • • Carbamazepine Valproic acid BDZs. New compounds: • • • • • • Felbamate Gabapentin Lamotrigine Tiagabine Topiramate Vigabatrin Pharmacokinetic Parameters TREATMENT OF SEIZURES Seizure disorder Drugs Tonic-clonic(Grand mal) Drug of Choice Carbamazepine or Valproate or Phenytoin or Phenobarbital Alternatives: Topiramte Lamotrigine (as adjunct or alone) Gabapentin (as adjunct) Partial (simple or complex) Drug of choice Carbamazepine or Topiramte or Phenytoin or Valproate Alternatives: Phenobarbital Lamotringine (as adjunct or alone) Gabapentin (as adjunct ) Treatament cont,d Absence ( petit mal) Drug of choice Valproate or Ethosuximide Alternatives: Clonazepam Lamotrigine Myoclonic, Atonic Drug of choice Valproate Alternatives: Clonazepam Status Epilepticus Drug of choice Diazepam, i.v. or Phenytoin, i.v. or Vaproate Alternatives: Phenobarbital, i.v Febrile Seizures Diazepam, rectal* Diazepam ,i.v Valproate * Preferred 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) 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. 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 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 % 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. The Cytochrome P-450 Enzyme System Inducers Inhibitors phenobarbital valproate primidone topiramate (CYP2C19) phenytoin oxcarbazepine (CYP2C19) carbamazepine felbamate (CYP2C19) felbamate (CYP3A) (increase phenytoin, topiramate (CYP3A) phenobarbital) oxcarbazepine (CYP3A) 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 Phenytoin ( Cont. ) Mechanism of Action: Membrane stabilization by blocking Na & Ca influx into the neuronal axon. or inhibits the release of excitatory amino acids via inhibition of Ca influx Clinical Uses: Used for partial Seizures & generalized tonic-clonic seizures. But not effective for absence Seizures . Also can be used for Rx of ventricular fibrillation. Side effects: Dose Related: • G.I.T upset • Neurological like headache, vertigo, ataxia, diplopia, nystagmus • Sedation Side effects of Phenytoin ( Cont. ) Non-dose related: • Gingival hyperplasia • Hirsutism • Megaloblastic anaemia • Hypersensitivity reactions (mainly skin rashes and lesions, mouth ulcer) • Hepatitis –rare • Fetal malformations- esp. cleft plate • Bleeding disorders (infants) • Osteomalacia due to abnormalities in vit D metabolism • Side effects of phenytoin ( Cont.) • Pharmacokinetic Interactions – Inhibitors of liver enzymes elevate its plasma levels e.g. Chloramphenicol, INH,cimetidine. – Inducers of liver enzymes reduce its plasma levels e.g. Carbamazipine; Rifampicin, phenobarbital. Fosphenytoin • A Prodrug. Given i.v. or i.m. and rapidly converted to phenytoin in the body. • Avoids local complications associated with phenytoin: vein irritation, tissue damage, pain and burning at site, muscle necrosis with i.m. injection, need for large fluid volumes. • Otherwise similar toxicities to phenytoin. CARBAMAZEPINE Its mechanism of action and clinical uses are similar to that of phenytoin. However, it is also commonly used for Rx of mania and trigeminal neuralgia. Pharmacokinetics available as an oral form only Well absorbed 80 % protein bound Strong inducing agent including its own (can lead to failure of other drugs e.g. oral contraceptives, warfarin, etc. Metabolized by the liver to CBZ 10.11-epioxide(active) and CBZ -10-11-dihydroxide (inactive) Pharmacokinetics of CBZ( Cont. ) • Excreted in urine as glucuronide conjugate • Plasma t1/2 approx. 30 hours • Therapeutic plasma concentration 6-12 µg/ml (narrow). • Dose 200-800 mg/day (given BID as sustained release form) • Side Effects of Carbamazepine: • • • • G.I upset Drowziness, ataxia and headache; diplopia Hepatotoxicity- rare Congenital malformation (craniofacial anomalies & neural tube defects). • Hyponatraemia & water intoxication. • Late hypersensitivity reaction (erythematous skin rashes, mouth ulceration and lymphadenopathy. • Blood dyscrasias as fetal aplastic anemia (stop medication); mild leukopenia (decrease the dose) Pharmacokinetic interactions of CBZ • Inducers of liver enzymes reduce its plasma level e.g. Phenytoin; Phenobarbital; Rifampicin • inhibitors of liver enzymes elevate its plasma levels e.g. erythromycin,INH ,verapamil; Cimetidine Phenobarbital Mechanism of Action: • Increases the inhibitory neurotransmitters (e.g: GABA ) and decreasing the excitatory transmission. • Also, it also prolongs the opening of Clchannels. • Absorption: rapid • Half-life: 53-118 hours (long) • Phenobarbital • Partial seizures, effective in neonates • Second-line drug in adults due to more severe CNS sedation • Adverse effects: CNS sedation but may produce excitement in some patients. Skin rashes if allergic. Tolerance and physical dependence possible. • Interactions: severe CNS depression when combined with alcohol or benzodiazapines. Stimulates cytochrome P-450 Primidone • Partial seizures • Mechanims—see phenobarbital • Absorption: Individual variability in rates. Not highly bound to plasma proteins. • Metabolism: Converted to phenobarbital and phenylethyl malonamide, 40% excreted unchanged. • Half-life: variable, 5-15 hours. • Adverse effects: CNS sedative • Drug interactions: enhances CNS depressants, drug metabolism, phenytoin increases conversion to PB Vigabatrin (restricted) Pharmacological effects:Drug of choice for infantile spasms, Use for partial seizures and West’s syndrome. • Not bound to proteins ,Not metabolized and excreted unchanged in urine • Plasma t1/2 4-7 hrs Side effects: Visual field defects, psychosis and depression (limits its use). VIGABATRIN (-vinyl-GABA) • Contraindicated if preexisting mental illness is present. Toxicity: •Drowsiness •Dizziness •Weight gain •Agitation •Confusion •Psychosis • Irreversible inhibitor of GABAaminotransferase (enzyme responsible for metabolism of GABA) => Increases inhibitory effects of GABA. Lamotrigine Pharmacological effects Resembles phenytoin in its pharmacological effects Well absorbed from GIT Metabolised primarily by glucuronidation Does not induce or inhibit C. P-450 isozymes ( its metabolism is inhibitted by valproate ) Plasma t 1/2 approx. 24 hrs. • Mechanism of Action: Inhibits excitatory amino acid release (glutamate & aspartate ) by blockade of Na channels. • Side effects: • Skin rash, somnolence, blurred vision, diplopia, ataxia, headache, aggression, influenza – like syndrome LAMOTRIGINE (Lamictal) Toxicity: •Dizziness •Headache •Diplopia •Nausea •Somnolence •Life threatening rash “StevensJohnson” • Add-on therapy with valproic acid (w/v.a. conc. have be reduced => reduced clearance). • Low plasma protein binding • Effective in myoclonic and generalized seizures in childhood and absence attacks. • Involves blockade of repetitive firing involving Na channels, like phenytoin. FELBAMATE Toxicity: •Aplastic anemia •Severe hepatitis • Effective against partial seizures but has severe side effects. • Because of its severe side effects, it has been relegated to a thirdline drug used only for refractory cases. Gabapentin • Structural analogue of GABA .May increase the activity of GABA or inhibits its re-uptake. Pharmacokinetics: Not bound to proteins Not metabolized and excreted unchanged in urine • Does not induce or inhibit hepatic enzymes (similar to lamotrigine) • Plasma t ½ 5-7 hours GABAPENTIN Toxicity: •Somnolence. •Dizziness. •Ataxia. •Headache. •Tremor. • Used as an adjunct in partial and generalized tonic-clonic seizures. • drug-drug interactions are negligible. • Low potency. • An a.a.. Analog of GABA that does not act on GABA receptors, it may however alter its metabolism, nonsynaptic release and transport. Topimerate • Add-on for refractory partial or generalized seizures. Effective as monotherapy for partial or generalized seizures, Lennox-Gastaut syndrome. • Use-dependent blockade of Na+ channels, increases frequency of GABAA channel openings, may interfere with glutamate binding to AMPA/KA receptor • Half-life: 20-30 hours (long) • Adverse effects: CNS sedative • Drug interactions: Stimulates CYP3A and inhibits CYP2C19, can lessen effectiveness of birth control pills Topiramate ( Cont. ) Clinical Uses: Recently, this drug become one of the safest antiepileptics which can be used alone for partial and generalized tonicclonic, and absence seizures. TIAGABINE (Gabatril) Toxicity: •Abdominal pain and nausea (must be taken w/food) •Dizziness •Nervousness •Tremor •Difficulty concentrating •Depression •Asthenia •Emotional liability •Psychosis •Skin rash • Adjunctive therapy in partial and generalized tonic-clonic seizures • Bioavailability > 90 % • Highly protein bound ( 96% ) • Metabolized in the liver • Plasma t ½ 4 -7 hrs • Mode of action: • inhibits GABA uptake and increases its level Zonisamide Pharmacokinetics: • • • • • Well absorbed from GIT (100 %) Protein binding 40% Extensively metabolized in the liver No effect on liver enzymes Plasma t ½ 50 -68 hrs Clinical Uses: Add-on therapy for partial seizures Side Effects: Drowsiness, ataxia , headache, loss of appetite,nausea& vomiting, Somnolence . Levetiracetam • Add-on therapy for partial seizures • Binds to synaptic vesicle protein SV2A, may regulate neurotransmitter release • Half-life: 6-8 hours (short) • Adverse effects: CNS depresssion • Drug interactions: minimal Ethosuximide • • • • Absence seizures Blocks T-type Ca++ currents in thalamus Half-life: long—40 hours Adverse effects: gastric distress—pain, nausea, vomiting. Less CNS effects that other AEDs, transient fatigue, dizziness, headache • Drug interactions: administration with valproate results in inhibition of its metabolism VALPROATE (Depakene) • Toxicity: •Elevated liver enzymes including own. • •Nausea and vomiting. •Abdominal pain and heartburn. • •Tremor, hair loss, • •Weight gain. •Idiosyncratic • hepatotoxicity. •Negative interactions with other antiepileptics. • •Teratogen: spina bifida Fully ionized at body pH, thus active form is valproate ion. Mechanism of action, similar to phenytoin. levels of GABA in brain. Facilitates Glutamic acid decarboxylase (GAD). Inhibits the GABA-transporter in neurons and glia (GAT). [aspartate]Brain? • May increase membrane potassium conductance. • Inhibits metabolism of several drugs such as Carbamazepine; phenytoin, Topiramate and phenobarbital. • Clinical Use: – Very effective against absence, myoclonic seizures. – Also, effective in gen. tonic-clonic siezures (primarly Gen) – Less effective as compared to carbamazepine for partial seizures – Like Carbamazepine also can be used for Rx of mania • Side Effects of Sod. valproate: • Nausea, vomiting and GIT disturbances (Start with low doses) • Increased appetite & weight gain • Transient hair loss. • Hepatotoxicity • Thrombocytopenia • Neural Tube defect (e.g. Spina bifida) in the offspring of women. (contraindicated in pregnancy) Status Epilepticus Status epilepticus exists when seizures recur within a short period of time , such that baseline consciousness is not regained between the seizures. They last for at least 30 minutes. Can lead to systemic hypoxia, acidemia, hyperpyrexia, cardiovascular collapse, and renal shutdown. • The most common, generalized tonic-clonic status epilepticus is life-threatening and must be treated immediately with concomitant cardiovascular, respiratory and metabolic management. Treatment of Status Epilepticus in Adults Initial • Diazepam, i.v. 5-10 mg (1-2 mg/min) repeat dose (5-10 mg) every 20-30 min. • Lorazepam, i.v. 2-6 mg (1 mg/min) repeat dose (2-6 mg) every 20-30 min. Follow-up • Phenytoin, i.v. 15-20 mg/Kg (30-50 mg/min). repeat dose (100-150 mg) every 30 min. • Phenobarbital, i.v. 10-20 mg/Kg (25-30mg/min). repeat dose (120-240 mg) every 20 min. DIAZEPAM AND LORAZEPAM Toxicity •Sedation •Children may manifest a paradoxical hyperactivity. •Tolerance • • • • Given I.V. Lorazepam may be longer acting. Have muscle relaxant activity. Allosteric modulators of GABA receptors. • Potentiate GABA function by increasing the frequency of channel opening. Treatment of Seizures PARTIAL SEIZURES ( Simple and Complex, including secondarily generalized) Drugs of choice: Carbamazepine Phenytoin Valproate Alternatives: Lamotrigine, phenobarbital, primidone, oxcarbamazepine. Add-on therapy: Gabapentin, topiramate, tiagabine, levetiracetam, zonisamide. Treatment of Seizures PRIMARY GENERALIZED TONIC-CLONIC SEIZURES (Grand Mal) Drugs of choice: Carbamazepine Phenytoin Valproate* Alternatives: Lamotrigine, phenobarbital, topiramate, oxcartbazepine, primidone, levetiracetam. *Not approved except if absence seizure is involved Treatment of Seizures GENERALIZED ABSENCE SEIZURES Drugs of choice: Ethosuximide Valproate* Alternatives: Lamotrigine, clonazepam, zonisamide, topiramate (?). * First choice if primary generalized tonic-clonic seizure is also present. Treatment of Seizures ATYPICAL ABSENCE, MYOCLONIC, ATONIC* SEIZURES Drugs of choice: Valproate Clonazepam Lamotrigine** Alternatives: Topiramate, clonazepam, zonisamide, felbamate. * Often refractory to medications. **Not FDA approved for this indication. May worsen myoclonus. Treatment of Seizures INFANTILE SPASMS Drugs of choice: Corticotropin (IM) or Corticosteroids (Prednisone) Zonisamide Alternatives: Clonazepam, nitrazepam, vigabatrin, phenobarbital. Treatment of Seizures in Pregnancy Phenytoin Carbamazepine Phenobarbital Primidone They may all cause hemorrhage in the infant due to vitamin K deficiency, requiring treatment of mother and newborn. They all have risks of congenital anomalies (oral cleft, cardiac and neural tube defects). Teratogens: Valproic acid causes spina bifida. Topiramate causes limb agenesis in rodents and hypospadias in male infants. Zonisamide is teratogenic in animals. INTERACTIONS BETWEEN ANTISEIZURE DRUGS With other antiepileptic Drugs: - Carbamazepine with phenytoin Increased metabolism of carbamazepine phenobarbital Increased metabolism of epoxide. - Phenytoin with primidone - Valproic acid with clonazepam phenobarbital phenytoin Increased conversion to phenobarbital. May precipitate nonconvulsive status epilepticus Decrease metabolism, increase toxicity. Displacement from binding, increase toxicity. ANTISEIZURE DRUG INTERACTIONS With other drugs: phenytoin, phenobarb, carb. phenytoin and phenobarb met. cimetidine displaces pheny, and BDZs isoniazid toxicity of phenytoin oral contraceptives antiepileptics metabolism. salicylates displaces phenytoin and v.a. theophyline carb and phenytoin may effect. antibiotics anticoagulants Table 2. Proposed Mechanisms of Antiepileptic Drug Action ↓Na+ ↓Ca+ ↓K+ ↑ Inh. ↓Excitatory channels channels channels transmission transmission ________________________________________________________________________________ Established AED’s PHT +++ CBZ +++ ESM +++ PB + +++ + BZD’s +++ VPA + + ++ + New AED’s LTG +++ + OXC +++ + + ZNS ++ ++ VGB +++ TGB +++ GBP + + ++ FBM ++ ++ ++ ++ TPM ++ ++ ++ ++ LEV + + + ________________________________________________________________________________ +++ primary action, ++ possible action, + probable action. From P. Kwan et al. (2001) Pharmacology and therapeutics 90:21-34. [Data from Upton (1994), Schachter (1995), McDonald and Kelly (1995), Meldrum (1996), Coulter (1997), and White (1999).] Weight Issues • Risk of weight gain – Valproate – Gabapentin and pregabalin • “Risk” of weight loss – Topiramate – Zonisamide – Felbamate Drugs that decrease efficacy of oral contraceptives • • • • • • Phenytoin Carbamazepine Phenobarbital Primidone Topiramate at higher doses Oxcarbazepine Lifestyle changes to minimize seizures • • • • Avoid sleep deprivation Avoid alcohol Treat fevers quickly Occasional patients should avoid specific factors such as strobe lights, etc • Pill boxes/reminders Herbal meds reported to worsen seizures • • • • • • • • • • • • • Bearberry Black cohosh Borage Damiana Echinacea Ephedra* Ergot Evening Primrose Oil Gingko (prob safe) Ginseng Goldenseal Green Tea Guarana • • • • • • • • • • • • • Histalet Forte Kava Kava Ma Huang* Metabolife Monkshood Phen-Fen* Sage St. John’s Wort Uva-Ursi Water-hemlock European water hemlock Wormwood Yohimbe Herbal meds with significant interactions with seizure meds • • • • • • • • • • • Chamomila Choke cherry Comfrey Dillapiol Echinacea Eucalyptus Oil Grapefruit juice Licorice Mentat Nicotinamide Paeoniae radix • • • • • • • • • Piperine Psyllium Pyrrolizidine Sage St. John’s Wort Septilin Shankapushpi Sho-seiryu-to Wild cherry