Pharmacology of Snc: Antiepileptic Drugs – A Seminar Presentation

EPILEPSY: Disorder of Brain Function

EPILEPSY: disorder of brain function characterized by the periodic and unpredictable occurrence of seizures. SEIZURE: transient alteration of behavior due to the disordered, synchronous, and rhythmic firing of populations of brain neurons - thought to arise from the cerebral cortex, and not from other CNS structures such as the thalamus, brainstem, or cerebellum. - behavioral manifestation: determined by the functions normally served by the cortical site at which the seizure arises (eg. seizure involving motor cortex > clonic jerking of the body part controlled by this region of cortex)

CLASSIFICATION of Seizures

Partial Seizures

• Simple : with preservation of consciousness.
• Complex : with impairment of consciousness

Generalized Seizures

Generalized seizures: those that involve both hemispheres widely from the outset

• Absence
• Myoclonic
• Tonic-clonic

Electroencephalography (EEG) Records in Epilepsy

A Normal B Generalised seizure (grand mal) - tonic-clonic type 1 2 3 4 F T C 1s F O O F · T T. c Generalised seizure (petit mal) - absence seizure type D Partial seizure 1 Rang et al: Rang & Dale's Pharmacology, 7e Copyright @ 2011 by Churchill Livingstone, an imprint of Elsevier Ltd. All rights reserved. Figure 44.1 Electroencephalography (EEG) records in epilepsy. [A] Normal EEG recorded from frontal (F), temporal (T) and occipital (O) sites on both sides, as shown in the inset diagram. The a rhythm (10/s) can be seen in the occipital region. [B] Sections of EEG recorded during a generalised tonic-clonic (grand mal) seizure: 1, normal record; 2, onset of tonic phase; 3, clonic phase; 4, postconvulsive coma. [C] Generalised absence seizure (petit mal) showing sudden brief episode of 3/s 'spike and wave' discharge. [D] Partial seizure with synchronous abnormal discharges in left frontal and temporal regions. (From Eliasson S G et al. 1978 Neurological pathophysiology, 2nd edn. Oxford University Press, New York.)

ANTISEIZURE DRUGS (ASD) Utilization in Spain

2008 2009 2010 2011 2012 2013 2014 2015 2016 Total Otros antiepilepticos 6,33 7,35 8,17 8,91 9,27 9,9 10,66 10,98 11,82 Estiripentol <0,01 Gabapentina 1,7 1,77 1,79 1,81 1,75 1,78 1,86 1,89 2 Lacosamida 0,01 0,07 0,11 0,15 0,19 0,23 0,28 0,34 Lamotrigina 0,84 0,9 0,91 0,92 0,9 0,91 0,94 0,94 0,99 Levetiracetam 0,73 1 1,26 1,52 1,71 1,92 2,14 2,27 2,49 Perampanel - - - - - - 0,04 0,07 0,1 Pregabalina 2,01 2,51 2,93 3,33 3,56 3,87 4,17 4,24 4,54 Retigabina Topiramato 0,95 1 1,01 1 0,96 0,96 0,97 0,94 0,96 Zonisamida 0,1 0,16 0,2 0,22 0,23 0,26 0,3 0,35 0,39 Total Derivados de carboxamida 2,2 2,28 2,24 2,2 2,12 2,1 2,13 2,1 2,17 Carbamazepina 1,15 1,15 1,12 1,08 1,01 0,98 0,96 0,92 0,92 Eslicarbazepina 0,04 0,11 0,15 0,21 0,27 0,34 Oxcarbazepina 1,04 1,12 1,11 1,07 0,99 0,96 0,95 0,9 0,9 Rufinamida <0,01 0,01 0,01 0,01 0,01 0,01 0,01 0,01 0,01 Total Derivados de ácidos grasos 1,78 1,88 1,91 1,93 1,89 1,92 1,96 1,93 1,97 Tiagabina 0,02 0,02 0,01 0,01 0,01 0,01 0,01 0,01 0,01 Valproico 1,68 1,78 1,82 1,84 1,81 1,84 1,88 1,85 1,92 Valpromida 0,06 0,06 0,06 0,06 0,05 0,05 0,05 0,05 0,02 Vigabatrina 0,02 0,02 0,02 0,02 0,02 0,02 0,02 0,02 0,02 Total Barbitúricos y derivados 1 1,01 0,98 0,93 0,87 0,84 0,81 0,77 0,76 Fenobarbital 0,94 0,93 0,9 0,85 0,78 0,75 0,72 0,68 0,66 Primidona 0,06 0,08 0,08 0,08 0,09 0,09 0,09 0,09 0,1 Total Derivados de benzodiazepina 0,61 0,67 0,71 0,75 0,77 0,82 0,9 0,94 1,05 Clonazepam 0,61 0,67 0,71 0,75 0,77 0,82 0,9 0,94 1,05 Total Derivados de hidantoína 0,98 0,94 0,86 0,78 0,69 0,62 0,58 0,52 0,49 Fenitoína 0,98 0,94 0,86 0,78 0,69 0,62 0,58 0,52 0,49 Total Derivados de succinimida 0,01 0,01 0,01 0,01 0,01 0,01 0,01 0,01 0,01 Etosuximida 0,01 0,01 0,01 0,01 0,01 0,01 0,01 0,01 0,01 Total general 12,91 14,14 14,88 15,51 15,62 16,21 17,05 17,25 18,27 - - - <0,01 0,01 0,01 0,01 <0,01 <0,01 - - - - - - - - - - - - - - - - <0,01 Brivaracetam - - - - Tabla 1. Utilización de antiepilépticos en España. Datos expresados en DDD/1.000 hab y día. Sistema Nacional de Salud

CLASSIFICATION OF EPILEPTIC SEIZURES and Treatments

TABLE 17-1 CLASSIFICATION OF EPILEPTIC SEIZURES SEIZURE TYPE FEATURES CONVENTIONAL ANTISEIZURE DRUGS RECENTLY DEVELOPED ANTISEIZURE DRUGS

Focal Seizures

Focal Aware Seizures

Diverse manifestations determined by the region of cortex activated by the seizure (e.g., if motor cortex representing left thumb, clonic jerking of left thumb results; if somatosensory cortex representing left thumb, paresthesia of left thumb results), lasting approximating 20-60 sec. Carbamazepine, phenytoin, valproate Brivaracetam, Key feature is preservation of awareness.

Focal with Impaired Awareness Seizures

Impaired consciousness lasting 30 sec to 2 min, often associated with purposeless movements such as lip smacking or hand wringing. Simple or complex focal seizure evolves into a tonic-clonic seizure with loss of awareness and sustained contractions (tonic) of muscles throughout the body, followed by periods of muscle contraction alternating with periods of relaxation (clonic), typically lasting 1-2 min. Carbamazepine, phenobarbital, phenytoin, primidone, valproate

Generalized Seizures

Generalized Absence Seizures

Abrupt onset of impaired consciousness associated with staring and cessation of ongoing activities, typically lasting less than 30 sec. Ethosuximide, valproate, Lamotrigine clonazepam

Generalized Myoclonic Seizures

A brief (perhaps a second), shock-like contraction of muscles that may be restricted to part of one extremity or may be generalized. Valproate, clonazepam Levetiracetam

Generalized Tonic-Clonic Seizures

As described above for partial with secondarily generalized tonic-clonic seizure except that it is not preceded by a partial seizure. Carbamazepine, phenobarbital, phenytoin, primidone, valproate Lamotrigine, levetiracetam, topiramate eslicarbazepine, ezogabine, gabapentin, lacosamide, lamotrigine, levetiracetam, perampanel, rufinamide, tiagabine, topiramate, zonisamide

Focal to Bilateral Tonic-Clonic Seizures

Current pharmacological treatments: · Symptomatic: inhibit seizures (Do they prevent the development of epilepsy (epileptogenesis)?) · Neither effective prophylaxis nor cure is available · Problem: compliance (need for long-term therapy together with unwanted effects of many drugs)

Mechanisms of Action of Antiseizure Drugs

GLUTAMATE Na+ + Ca2+ a GABA Cl -The mechanisms of action of antiseizure drugs (ASDs) fall into these major categories:

1. Modulation of cation channels (Na+, K+, Ca2+). This can include prolongation of the inactivated state of voltage-gated Na+ channels, positive modulation of K+ channels, and inhibition of Ca2+ channels.
2. Enhancement of GABA neurotransmission through actions on GABAA receptors, modulation of GABA metabolism, and inhibition of GABA reuptake into the synaptic terminal.
3. Modulation of synaptic release through actions on the synaptic vesicle protein SV2A or Ca2+ channels containing the a28 subunit.
4. Diminishing synaptic excitation mediated by ionotropic glutamate receptors (e.g., AMPA receptors).

BUT Many ASDs act through mechanisms distinct from the primary known mode of action ASDs with similar mechanistic categories may have disparate clinical uses

GLUTAMATERGIC EXCITATORY SYNAPSIS

mGluR3 BY Presynaptic nerve terminal mGluR2 O VG-Ca".(N) 2 NTFS - K 4 Trk CRMP-2 U SV,A 5 BY Glia VG-Ca2+(P/Q) EAAT mGluR7,8 O o O O O EAAT O 6 mGluR3 NMDA AMPA O mGluR5 mGluR1 Y BY D Postsynaptic cell VG-Ca2.(T) 2 AMPA VG-Na' VG-Na*

Presynaptic Targets Diminishing Glutamate Transmission

1. Voltage-gated (VG) Na+ channels
2. VG-Ca2+ channels
3. K+ channels
4. Synaptic vesicle proteins (SV2A)

Postsynaptic Targets

1. AMPA receptors (Na+ channels)
2. NMDA receptors (Ca2+ channels)

Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, VG-Na 1 3 O

Voltage-activated Na+ channels and ASDs

Open Inactivated Voltage-activated Na+ channels Na+ Na+ A A I 1 carbamazepine phenytoin topiramate Na+ Na+ lacosamide lamotrigine valproate zonisamide Figure 17-2 Antiseizure drug-enhanced Na+ channel inactivation. Some anti- seizure drugs (noted in blue text) prolong the inactivation of the Na+ channels, thereby reducing the ability of neurons to fire at high frequencies. The inacti- vated channel itself appears to remain open but is blocked by the inactivation gate, I. Activation gate, A. Goodman&Gilman (13th Ed)

Proposed Mechanisms of Action of Antiseizure Drugs

PHT - PHENYTOIN CBZ - CARBAMAZEPINE ExCBZ - OXCARBAZEPINE ESL - ESLICARBAZEPINE RUF - RUFINAMIDE VPA - VALPROATE LTG - LAMOTRIGINE TPM - TOPIRAMATE LCM - LACOSAMIDE TABLE 17-2 PROPOSED MECHANISMS OF ACTION OF ANTISEIZURE DRUGS MOLECULAR TARGET AND ACTIVITY DRUG CONSEQUENCES OF ACTION

Na+ Channel Modulators

Na+ channel modulators that: Enhance fast inactivation PHT, CBZ, LTG, FBM, OxCBZ, TPM, VPA, ESL, RUF · Block action potential propagation · Stabilize neuronal membranes · V Neurotransmitter release, focal firing, and seizure spread Enhance slow inactivation LCM · Î Spike frequency adaptation · V Action potential bursts, focal firing, and seizure spread · Stabilize neuronal membrane

USE-DEPENDENT BLOCKADE

Voltage-activated Na+ channels USE-DEPENDENT BLOCKADE Resting Open Inactivated Favoured by depolarisation Na+ fast slow - Inactivating particle Blocking drug 1 1 A 1 B C They preferentially bind to inactivated channels > prevent their return to resting state reduce the number of functional channels available to generate action potentials

Voltage-activated Ca2+ channels and ASDs

Voltage-activated Ca2+ channels Ca2+ Ca2+ ethosuximide valproate Ca2+ Ca2+ Figure 17-4 Antiseizure drug-induced reduction of current through T-type Ca2+ channels. Some antiseizure drugs (e.g., valproate and ethosuximide) reduce the flow of Ca2+ through T-type Ca2+ channels, thereby reducing the pace- maker current that underlies the thalamic rhythm in spikes and waves seen in generalized absence seizures. VPA - VALPROATE ESM - ETHOSUXIMIDE LTG - LAMOTRIGINE

Ca2+ Channel Blockers

Ca2+ channel blockers ESM, VPA, LTG · V Neurotransmitter release (N- and P- types) · V Slow-depolarization (T-type) and spike-wave discharges

Ligand-operated Na+ and Ca2+ channels

Ligand-operated Na+ and Ca2+ channels O O Ca2+ Na+ O O O 6 7 NMDA AMPA PB - PHENOBARBITAL TPM - TOPIRAMATE PER - PERAMPANEL FBM - FELBAMATE (not in Spain)

NMDA Receptor Antagonists

NMDA receptor antagonists FBM · J Slow excitatory neurotransmission · V Excitatory amino acid neurotoxicity · Delay epileptogenesis

AMPA/Kainate Receptor Antagonists

AMPA/kainate receptor antagonists PB, TPM, PER · V Fast excitatory neurotransmission and focal firing