Slide 2: Brain regions and neuronal pathways Certain parts of the brain govern specific functions. Point to sensory, motor, association and visual cortex to highlight specific functions. Point to the cerebellum for coordination and to the hippocampus for memory. Indicate that nerve cells or neurons travel from one area to another via pathways to send and integrate information. Show, for example, the reward pathway. Start at the ventral tegmental area (VTA) (in magenta), follow the neuron to the nucleus accumbens, and then on to prefrontal cortex. Explain that this pathway gets activated when a person receives positive reinforcement for certain behaviors (&quot;reward&quot;). Indicate that you will explain how this happens when a person takes an addictive drug.
ANTIEPILEPTIC DRUGS Martha I. Dávila-García, Ph.D. Howard University Department of Pharmacology
EpilepsyA 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.
Epilepsy• There are 2.5 million Americans with epilepsy in the US alone.• More than 40 forms of epilepsy have been identified.• Therapy is symptomatic in that the majority of drugs prevent seizures, but neither effective prophylaxis or cure is available.
Seizures• The causes for seizures can be multiple, from infection, to neoplasms, to head injury. In a few subgroups it is an inherited disorder.• Febrile seizures or seizures caused by meningitis are treated by antiepileptic drugs, although they are not considered epilepsy (unless they develop into chronic seizures).• Seizures may also be caused by acute underlying toxic or metabolic disorders, in which case the therapy should be directed towards the specific abnormality.
Neuronal Substrates of Epilepsy The Synapse ionsThe Brain The Ion Channels/Receptors
Classification of Epileptic SeizuresI. Partial (focal) Seizures A. Simple Partial Seizures B. Complex Partial SeizuresII. Generalized Seizures A. Generalized Tonic-Clonic Seizures B. Absence Seizures C. Tonic Seizures D. Atonic Seizures E. Clonic Seizures F. Myoclonic Seizures G. Infantile Spasms
Scheme of Seizure Spread Simple (Focal) Partial SeizuresContralateral spread
I. Partial (Focal) SeizuresA. 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.
I. Partial (focal) SeizuresB. 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 SeizuresIn 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 SeizuresA. Generalized Tonic-Clonic Seizures Recruitment of neurons throughout the cerebrumMajor convulsions, usually with two phases: 1) Tonic phase 2) Clonic phaseConvulsions: – 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, and Absence Seizures are non-convulsive
II. Generalized SeizuresNeuronal Correlates of Paroxysmal Discharges Generalized Tonic-Clonic Seizures
II. Generalized SeizuresA. Generalized Tonic-Clonic SeizuresTonic 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 SeizuresA. Generalized Tonic-Clonic SeizuresClonic 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
II. Generalized SeizuresB. Absence Seizures (Petite Mal)• Brief and abrupt loss of consciousness, vacant stare.• Sometimes with no motor manifestations.• Minor muscular twitching restricted to eyelids (eyelid flutter) and face.• 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.• No loss of postural control.
II. Generalized SeizuresNeuronal Correlates of Paroxysmal Discharges Generalized Absence Seizures
II. Generalized SeizuresB. Absence Seizures (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-wave phase: Neurons generate short duration depolarization and a burst of action potentials, but there is no sustained depolarization or repetitive firing of action potentials.
Scheme of Seizure Spread Primary Generalized Absence Seizures Thalamocortial relays are believed to act on a hyperexcitable cortex
II. Generalized SeizureC. Tonic Seizures• Opisthotonus, loss of consciousness.• Marked autonomic manifestations
II. Generalized SeizureC. Tonic Seizures• Opisthotonus, loss of consciousness.• Marked autonomic manifestationsD. Atonic Seizures (atypical)• Loss of postural tone, with sagging of the head or falling.• May loose consciousness.
II. Generalized SeizureE. Clonic Seizures• Clonic Seizures: Rhythmic clonic contractions of all muscles, loss of consciousness, and marked autonomic manifestations.F. Myoclonic Seizures• Myoclonic Seizures: Isolated clonic jerks associated with brief bursts of multiple spikes in the EEG.
II. Generalized SeizuresF. 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.
Cellular and Synaptic Mechanisms of Epileptic Seizures(From Brody et al., 1997)
Treatment of SeizuresGoals:• 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 SeizuresStrategies:• Modification of ion conductances.• Increase inhibitory (GABAergic) transmission.• Decrease excitatory (glutamatergic) activity.
Actions of Phenytoin on Na+ Channels Na+B. Resting StateD. Arrival of Action Potential causes Na+ depolarization and channel opens allowing sodium to flow in. Na+ Sustain channel inF. Refractory State, this conformation Inactivation
Ca Channels 2+ Ion Channels Ca 2+ • Voltage-gated • Multiple Ca2+ mediated B events • Missense mutations of the T-type Ca-channel α1H subunit is associated with Childhood Absence Epilepsy in NorthernΨ: sites of N-linked glycosylation. ChinaP: cAMP-dependent protein kinase Drugs Used: phosphorylation sites • Calcium Channel Blockers
GABAergic SYNAPSE Drugs that Act at the GABAergic Synapse • GABA agonists • GABA antagonists • Barbiturates • Benzodiazepines • GABA uptake inhibitors Goal : GABA Activity
GLUTAMATERGIC SYNAPSE • Excitatory Synapse. • Permeable to Na+, Ca2+ and Na+ K+. Ca2+ AGONISTS • Magnesium ions block GLU channel in resting state.GLY • Glycine (GLY) binding enhances the ability of GLU or NMDA to open the channel. • Agonists: NMDA, AMPA, Mg++ Kianate. Goal: GLU Activity K +
Treatment of SeizuresMost 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.
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, butan alkyl group (ethosuximide) confers activity against generalized absence seizures.
Effects of three antiepileptic drugs on high frequency discharge of cultured neurons.Block of sustained high frequency repetitive firing of action potentials. (From Katzung B.G., 2001)
PHENYTOIN (Dilantin) • Oldest nonsedative antiepileptic drug. • Fosphenytoin, a more solubleToxicity: prodrug is used for parenteral•Ataxia and nystagmus. use.•Cognitive impairment. • “Fetal hydantoin syndrome”•Hirsutism • It alters Na+, Ca2+ and K+•Gingival hyperplasia.•Coarsening of facial conductances.features. • Inhibits high frequency•Dose-dependent zero order repetitive firing.kinetics. • Alters membrane potentials.•Exacerbates absence • Alters a.a. concentration.seizures. • Alters NTs (NE, ACh, GABA)
Fetal Hydantoin Syndrome• Pre- and postnatal growth deficiency with psychomotor retardation, microcephaly with a ridged metopic suture, hypoplasia of the nails and finger-like thumb and hypoplasia of the distal phalanges.• Radiological skeletal abnormalities reflect the hypoplasia and fused metopic suture.• Cardiac defects and abnormal genitalia.Teratogenicity of several anticonvulsant medications is associated with an elevated level of oxidative metabolites that are normally eliminated by the enzyme epoxide hydrolase.
CARBAMAZEPINE (Tegretol) • Tricyclic, antidepressant (bipolar) • 3-D conformation similar to phenytoin. • Mechanism of action, similar to phenytoin. Inhibits high frequency repetitive firing.Toxicity: • Decreases synaptic activity•Autoinduction of presynaptically.metabolism. • Binds to adenosine receptors (?).•Nausea and visualdisturbances. • Inh. uptake and release of NE, but•Granulocyte supression. not GABA.•Aplastic anemia. • Potentiates postsynaptic effects of•Exacerbates absence GABA.seizures. • Metabolite is active.
OXCARBAZEPINE (Trileptal) • Closely related to carbamazepine. • With improved toxicity profile. • Less potent than carbamazepine.Toxicity:•Hyponatremia • Active metabolite.•Less hypersensitivity • Mechanism of action, similarand induction of hepaticenzymes than with carb. to carbamazepine It alters Na+ conductance and inhibits high frequency repetitive firing.
PHENOBARBITAL (Luminal) • Except for the bromides, it is the oldest antiepileptic drug. • Although considered one of the safest drugs, it has sedative effects. • Many consider them the drugs of choice for seizures only in infants.Toxicity:• Sedation. • Acid-base balance important.• Cognitive • Useful for partial, generalized tonic- impairment. clonic seizures, and febrile seizures• Behavioral changes. • Prolongs opening of Cl- channels.• Induction of liver enzymes. • Blocks excitatory GLU (AMPA)• May worsen absence responses. Blocks Ca currents (L,N). 2+ and atonic seizures. • Inhibits high frequency, repetitive firing of neurons only at high concentrations.
PRIMIDONE (Mysolin) • Metabolized to phenobarbital and phenylethylmalonamide (PEMA), both active metabolites. • Effective against partial and generalized tonic-clonic seizures. • Absorbed completely, lowToxicity: binding to plasma proteins.•Same as phenobarbital • Should be started slowly to avoid•Sedation occurs early. sedation and GI problems.•Gastrointestinal complaints. • Its mechanism of action may be closer to phenytoin than the barbiturates.
VALPROATE (Depakene) • Fully ionized at body pH, thus active form is valproate ion. • One of a series of carboxylic acidsToxicity:•Elevated liver enzymes with antiepileptic activity. Itsincluding own. amides and esters are also active.•Nausea and vomiting. • Mechanism of action, similar to•Abdominal pain and phenytoin.heartburn.•Tremor, hair loss, ∀ ⇑ levels of GABA in brain.•Weight gain. • May facilitate Glutamic acid•Idiosyncratic decarboxylase (GAD). hepatotoxicity.•Negative interactions with• Inhibits GAT-1. ⇓ [aspartate]Brain?other antiepileptics. • May increase membrane potassium•Teratogen: spina bifida conductance.
ETHOSUXIMIDE (Zarontin) • Drug of choice for absence seizures. • High efficacy and safety. • VD = TBW. • Not plasma protein or fat binding • Mechanism of action involvesToxicity:•Gastric distress, reducing low-threshold Ca2+ channelincluding, pain, nausea current (T-type channel) in thalamus.and vomiting At high concentrations:•Lethargy and fatigue • Inhibits Na+/K+ ATPase.•Headache•Hiccups • Depresses cerebral metabolic rate.•Euphoria • Inhibits GABA aminotransferase.•Skin rashes • Phensuximide = less effective•Lupus erythematosus (?) • Methsuximide = more toxic
CLONAZEPAM (Klonopin) • A benzodiazepine. • Long acting drug with efficacy for absence seizures. • One of the most potent antiepileptic agents known. • Also effective in some cases ofToxicity: myoclonic seizures.• Sedation is prominent. • Has been tried in infantile• Ataxia. spasms.• Behavior disorders. • Doses should start small. • Increases the frequency of Cl- channel opening.
VIGABATRIN (γ-vinyl-GABA) • Absorption is rapid, bioavailability is ~ 60%, T 1/2 6-8 hrs, eliminated by the kidneys. • Use for partial seizures and West’s syndrome. • Contraindicated if preexistingToxicity:•Drowsiness mental illness is present.•Dizziness • Irreversible inhibitor of GABA-•Weight gain aminotransferase (enzyme responsible for metabolism of•Agitation GABA) => Increases inhibitory•Confusion effects of GABA.•Psychosis • S(+) enantiomer is active.
LAMOTRIGINE (Lamictal) • Presently use as add-on therapy with valproic acid (v.a. conc. are be reduced). • Almost completely absorbed • T1/2 = 24 hrs • Low plasma protein binding • Also effective in myoclonic andToxicity: generalized seizures in childhood and•Dizziness absence attacks.•Headache•Diplopia • Suppresses sustained rapid firing of•Nausea neurons and produces a voltage and use-•Somnolence dependent inactivation of sodium•Rash channels, thus its efficacy in partial seizures.
FELBAMATE (Felbatrol) • Effective against partial seizures but has severe side effects. • Because of its severe side effects, it has been relegated to a third-line drug used only for refractory cases.Toxicity:•Aplastic anemia•Severe hepatitis
TOPIRAMATE (Topamax) • Rapidly absorbed, bioav. is > 80%, has no active metabolites, excreted in urine.T1/2 = 20-30 hrs • Blocks repetitive firing of cultured neurons, thus its mechanism may involve blockingToxicity: of voltage-dependent sodium• Somnolence channels• Fatigue • Potentiates inhibitory effects of• Dizziness GABA (acting at a site different• Cognitive slowing from BDZs and BARBs).• Paresthesias• Nervousness • Depresses excitatory action of• Confusion kainate on AMPA receptors.• Urolithiasis • Teratogenic in animal models.
ZONISAMIDE (Zonegran) • Sulfonamide derivative. • Marketed in Japan. • Good bioavailability, low pb. • T1/2 = 1 - 3 days • Effective against partial and generalized tonic-clonicToxicity: seizures.•Drowsiness • Mechanism of action involves•Cognitive voltage and use-dependentimpairment inactivation of sodium channels•High incidence of (?).renal stones (?). • May also involve Ca2+ channels.
GABAPENTIN (Neurontin) • Used as an adjunct in partial and generalized tonic-clonic seizures. • Does not induce liver enzymes. • not bound to plasma proteins. • drug-drug interactions areToxicity: negligible.•Somnolence.•Dizziness. • Low potency.•Ataxia. • An a.a.. Analog of GABA that•Headache. does not act on GABA receptors, it•Tremor. may however alter its metabolism, non-synaptic release and transport.
Status EpilepticusStatus 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.
DIAZEPAM (Valium) AND LORAZEPAM (Ativan) • Benzodiazepines. • Will also be discussed with Sedative hypnotics.Toxicity • Given I.V.•Sedation•Children may • Lorazepam may be longer acting.manifest a • 1° for treating status epilepticusparadoxical • Have muscle relaxant activity.hyperactivity. • Allosteric modulators of GABA•Tolerance receptors. • Potentiates GABA function, by increasing the frequency of channel opening.
Treatment of Status Epilepticus in AdultsInitial• 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.
Treatment of SeizuresPARTIAL 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 SeizuresPRIMARY GENERALIZED TONIC- CLONIC SEIZURES (Grand Mal) Drugs of choice: Carbamazepine Phenytoin Valproate* Alternatives: Lamotrigine, phenobarbital, topiramate, oxcartbazepine, primidone, levetiracetam, phenobarbital. *Not approved except if absence seizure is involved
Treatment of SeizuresGENERALIZED 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 SeizuresATYPICAL ABSENCE, MYOCLONIC, ATONIC* SEIZURES Drugs of choice: Valproate** Lamotrigine*** Alternatives: Topiramate, clonazepam, zonisamide, felbamate.* Often refractory to medications.**Not approved except if absence seizure is involved.*** Not FDA approved for this indication.
Treatment of SeizuresINFANTILE SPASMS Drugs of choice: Corticotropin (IM) or Corticosteroids (Prednisone) Zonisamide Alternatives: Clonazepam, nitrazepam, vigabatrin, phenobarbital.
Infantile Spasms• Infantile spasms are an epileptic syndrome and not a seizure type.• The attacks although sometimes fragmentary are most often bilateral and are included, for pragmatic purposes, with the generalized seizures.• Characterized by recurrent myoclonic jerks with sudden flexion or extension of the body and limbs; the form of infantile spasms are, however, quite heterogeneous.• 90% have their first attack before the age of 1 year.• Most patients are mentally retarded, presumably from the same cause of the spasms.• The cause is unknown. Infections, kernicterus, tuberous sclerosis and hypoglycemia have all been implicated.
INTERACTIONS BETWEEN ANTISEIZURE DRUGSWith other antiepileptic Drugs:- Carbamazepine with phenytoin Increased metabolism of carbamazepine phenobarbital Increased metabolism of epoxide.- Phenytoin with primidone Increased conversion to phenobarbital.- Valproic acid with clonazepam May precipitate nonconvulsive status epilepticus phenobarbital Decrease metabolism, increase toxicity. phenytoin Displacement from binding, increase toxicity.
ANTISEIZURE DRUG INTERACTIONSWith other drugs:antibiotics phenytoin, phenobarb, carb.anticoagulants phenytoin and phenobarb met.cimetidine displaces pheny, v.a. and BDZsisoniazid toxicity of phenytoinoral contraceptives antiepileptics metabolism.salicylates displaces phenytoin and v.a.theophyline carb and phenytoin may effect.