PM 719 Pharmacology II Antiseizure Drugs PDF Lecture Notes

1 PM 719 Pharmacology II Lecture Notes (LN) Chapter 24 Antiseizure Drugs Epilepsy (a) 1% of the world’s population (b) 500 000 patients in US alone have uncontrolled epilepsy (c) drugs work in about 80% of patients (d) seizures = episodes of brai...

1 PM 719 Pharmacology II Lecture Notes (LN) Chapter 24 Antiseizure Drugs Epilepsy (a) 1% of the world’s population (b) 500 000 patients in US alone have uncontrolled epilepsy (c) drugs work in about 80% of patients (d) seizures = episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons (e) causes range from neoplasm, head injury, fever to unknown (f) in most cases the drug choice is determined by the type of epilepsy Drug Development (a) three approaches to drug discovery (1) drugs that enhance GABA transmission (inhibitory) (2) drug that diminish excitatory transmission (glutamate) (3) drugs that modify ionic conductance (b) all current drugs are palliative rather than curative Basic Pharmacology of Antiseizure Drugs Chemistry (a) 16 different drugs approved for treating epilepsy (b) 13 fall into the following chemical categories (1) barbiturates (2) hydantoins (3) oxazolidinediones (4) succinimides (5) acetylureas  2 Drugs Used in Partial Seizures & Generalized Tonic-Clonic Seizures All required drugs are in bold (a) Phenytoin and Fosphenytoin (1) also known as diphenylhydantoin (2) the first antiseizure drug that did not have sedative properties (discovered in 1938) (3) fosphenytoin, a prodrug, prevents the problems of im and iv injection of phenytoin (pain at the injection site) (4) mechanism is to block repetitive firing of action potentials (5) also blocks sodium channels in axons (6) metabolism follows first order kinetics (7) Therapeutic Levels & Dosage (a) for most patients therapeutic levels 10-20 ug/mL (b) increase dose in increments (25-30 mg) after a loading dose of 300 mg, not by 100 mg which leads to toxicity (first order kinetics) (8) phenytoin is 90% protein bound, sulfonamides can displace phenytoin from protein which increases free drug levels (9) most common ADR is diplopia (double vision) and ataxia (10) gingival hyperplasia occurs in most patients (11) Fosphenytoin, the prodrug of phenytoin. Very interesting. (b) Carbamazepine (1) tricyclic compound (2) 3-dimensional spatial conformation structure resembles phenytoin (3) mechanism similar to phenytoin (4) blocks sodium channels at therapeutic doses (5) drug 70% protein bound (6) drug induces microsomal liver enzymes (CYP) and half life can decrease from 36 hours to 8-12 hours after chronic usage (7) therapeutic levels must be measured often (8) most common ADRs are diplopia and ataxia (9) most common idiosyncratic reaction is an erythematous skin rash (c) Phenobarbital (1) oldest of the antiseizure drugs next to bromide (2) derivatives (1) mephobarbital (methylated phenobarbital) (2) metharbital (methylated barbital)  3 (3) primidone (3) mechanism of action: prolong opening of GABA receptor and effect on sodium channels (d) Primidone (1) biotransformed into two active metabolites: phenobarbital and phenylethylmalonamide (PEMA) (2) primidone acts through mechanisms like phenytoin (3) 70% free unbound drug (4) provides therapeutic levels of phenobarbital (5) ADRs are due to phenobarbital (e) Vigabatrin (1) irreversible inhibitor of GABA aminotransferase (GABA-T) the enzyme that degrades GABA (2) drug increases the levels of GABA in the brain (3) major ADR, visual field disturbances in up to one third of patients (4) visual disturbance is irreversible and drug used only when all others fail (f) Lamotrigine (1) acts at the level of sodium channels (block sodium channels) (2) also decreases the synaptic release of glutamate (3) widely used for partial seizures (4) ADRs include diplopia, rash, headache, somnolence (g) Gabapentin & Pregabalin (1) gabapentin is an analog of GABA (2) pregabalin is another analog of GABA (3) neither one acts directly on GABA receptors (4) gabapentin transported into the brain by means of the L-amino acid transporter (5) brain levels of GABA increase (6) both drugs bind avidly to alpha 2 gamma subunit of voltage gated Ca channels (7) decrease in Ca entry reduces release of glutamate in the brain (8) most common ADRs are somnolence, dizziness, ataxia, headache, and tremor (9) pregabalin approved to treat peripheral neuropathy (podiatry) (h) Lacosamide (1) amino acid derivative (2) slows activation of Na channels  4 (i) Levetiracetam (1) modifies synaptic release of GABA and glutamate from storage vesicles (j) Tiagabine (1) drug inhibits GABA uptake (2) drug increases GABA levels in brain (3) Developed through rational drug design (k) Topiramate (1) substituted monosaccharide (2) may block sodium channels (3) may potentiate inhibitory effects of GABA (l) Zonisamide (1) a sulfonamide derivative (2) acts on sodium channels Drugs Used In Generalized Seizures (m) Ethosuximide (1) cyclic ureide structure (2) acts on calcium currents (3) effective for absence seizures (4) gastric distress most common ADR (n) Valproic Acid & Sodium Valproate (1) discovered when used as a solvent (drug vehicle) in drug studies (2) a fatty carboxylic acid derivative (3) may block sodium currents (4) effective against absence seizures (5) drug displaces phenytoin from protein binding sites (6) major ADR is idiosyncratic hepatic toxicity with 50 deaths in the US (0) Benzodiazepines (a) diazepam used iv to treat status epilepticus (b) lorazepam used to treat status epilepticus (c) clonazepam for absence seizures (d) tolerance and sedative effects are major ADR  5 Summary of Mechanisms: Plug in any other drugs from the required drugs above which may not be in the list below. (1) Drugs act on voltage gated sodium channels (block Na+ channels) and decrease release of glutamate phenytoin carbamazepine valproate lamotrigine lacosamide fosphenytoin (2) Drugs act on synaptic protein SV2A and modify release of glutamate levetiracetam (3) Drugs reduce calcium currents (T-type) and decrease Ca++ entry ethosuximide gabapentin pregabalin (4) Drugs alter the phosphorylation state at the synapse and block Na channels topiramate (5) Drugs that act on GABA (a) Drugs enhance the response of GABAA receptors to GABA phenobarbital primidone clonazepam diazepam lorazapam (b) Drugs inhibit GABA-transaminase and raise GABA levels vigabatrin (c) Drugs block GABA re-uptake tiagabine  6 (6) Drugs that act through an unknonw MOA The drug cannabidiol, is a non-psychoactive drug derived from Cannabis sativa (pot). The drug does not act on the actual cannabinoid receptors but how it acts for seizure control is unknown. Used to treat a wide range of seizure disorders in infants, some of which are genetic in origin. Drug Classification Based on MOA (1) Drugs act on voltage gated sodium channels (block Na+ channels) and decrease release of glutamate phenytoin carbamazepine valproate oxcarbazepine lamotrigine lacosamide fosphenytoin (2) Drugs act on synaptic protein SV2A and modify release of glutamate levetiracetam (3) Drugs enhance the opening of potassium channels retigabine (4) Drugs reduce calcium currents (T-type) and decrease Ca++ entry ethosuximide gabapentin pregabalin (5) Drugs alter the phosphorylation state at the synapse topiramate (6) Drugs that act on GABA (a) Drugs enhance the response of GABAA receptors to GABA phenobarbital primidone clonazepam diazepam lorazapam  7 (b) Drugs inhibit GABA-transaminase and raise GABA levels vigabatrin (c) Drugs block GABA re-uptake tiagabine Antiseizure Drugs Organized by Drug Class (1) Barbiturates phenobarbital GABAA like all barbiturates, but strong blocking actions on sodium channels sodium channels...think how all local anesthetics work and how the propagation of electrical signals (conduction) are blocked. primidone prodrug converted to phenobarbital do not assume prodrugs are not important assume prodrugs are important pentobarbital OK, two more analogs of phenobarbital mephobarbital (2) Phenytoin and Derivatives phenytoin first non-sedating anticonvulsant major paradigm shift (what?) acts mostly by blocking sodium channels fosphenytoin prodrug of phenytoin here’s that prodrug stuff again mephenytoin two analogs of phenytoin ethotoin both have “toin” in their name easy (3) Benzodiazepines  8 diazepam haven’t we done these “lam” and “pam” drugs before? all act on GABA receptors, increase chloride influx, high doses stop seizures clonazepam OK, I get it, same as diazepam with some lorazepam differences that the book will explain clorazepate prodrug converted into a “pam” more prodrug stuff (4) Tricyclics carbamazipine all are “pine” drugs oxcarbazepine all block sodium channels eslicarbazepine this sounds familiar (5) GABA derivatives gabapentin all have some part of GABA in their name pregabalin if GABA is so important in making neurons vigabatrin quiet, then lets make some drugs that look like and act like GABA but, that turns out to be not exactly correct gabapentin and pregablin block calcium channels vigabatin inhibits the enzyme that removes GABA smells like a test question to me tiagabine blocks the re-uptake of GABA (6) Valproic Acid valproic acid a drug solvent that blocks sodium channels (7) Misc Sodium Channel Blockers lamotrigine three “mides” and one “gine” rufinamide all act by blocking sodium channels zonisamide lacosamide (8) Topiramate acts on phosphorylation step that’s something different  9 (9) Retigabine enhances potassium channel opening does that mean potassium flows in or out? do I have to read the book? (10) Felbamate potentiate GABAA; block NMDA receptors (11) Cyclic ureide analogs ethosuximide reduce low-threshold (T-type) calcium currents phensuximide methosuximide Antiseizuree Drugs Organized by MOA (1) Drugs act on voltage gated sodium channels (block Na+ channels) and decrease release of glutamate phenytoin carbamazepine valproate oxcarbazepine lamotrigine lacosamide fosphenytoin (2) Drugs act on synaptic protein SV2A and modify release of glutamate levetiracetam (3) Drugs enhance the opening of potassium channels retigabine (4) Drugs reduce calcium currents (T-type) and decrease Ca++ entry ethosuximide gabapentin pregabalin (5) Drugs alter the phosphorylation state at the synapse topiramate (6) Drugs that act on GABA (a) Drugs enhance the response of GABAA receptors to GABA  10 phenobarbital primidone clonazepam diazepam lorazapam (b) Drugs inhibit GABA-transaminase and raise GABA levels vigabatrin (c) Drugs block GABA re-uptake tiagabine Antiseizure Drugs Based on Drug Structure Cyclic Ureides phenytoin first antiseizure drug with reduced sedative properties blocks Na voltage gated channels mephenytoin “ “ “ ethotoin “ “ “ (ETH oh toyn) fosphenytoin pro-drug of phenytoin, new, big deal primidone phenobarbital pro-drug (PRI mi done) phenobarbital enhances GABAA response pentobarbital “ “ “ mephobarbital “ “ “ ethosuximide redcues Ca currents (T-type) (eth oh SUKS i mide) methsuximide “ “ “ Tricyclics carbamazepine acts on Na channels (kar ba MAZ e peen) oxcarbazepine “ “ eslicarbazepine “ “ Benzodiazepines diazepam potentiates GABAA response clonazepam “ “ “ lorazepam “ “ “ clorazepate “ “ “  11 clobazam not a benzo, a benzo derivative GABA Derivatives gabapentin acts on Ca channels (most widely used drug for DPN in podiatry) pregabalin acts on CA channels vigabatin inhibits GABA transaminase Other valproate blocks neuron high frequency firing lamotrigine inactivates Na channels (la MOE tri jeen) levetiracetam acts on synaptic proteins (lee va tye RA se tam) ezogabine enhance K channel currents (e ZOG a been) rufinamide prolong activation of Na channels tiagabine blocks reuptake of GABA (tye AG a been) topiramate acts on phosphorylation (?) zonisamide blocks high frequency firing of Na channels lacosamide enhances slow activation of Na channels felbamate acts on GABAA and NMDA receptors trimethadione acts on Ca channels perampanel AMPA receptor antagonist stiripentol enhances GABA transmission, compassionate use for certain types of epilepsy in infancy