Lecture 6: Antiepileptic Drugs PDF

Antiepileptic Drugs Seizure Epilepsy Convulsions A seizure is a sudden It is a disease Involuntary, violent and alteration in the brain characterized by spasmodic contractions of function (motor function, recurrent seizure...

Antiepileptic Drugs Seizure Epilepsy Convulsions A seizure is a sudden It is a disease Involuntary, violent and alteration in the brain characterized by spasmodic contractions of function (motor function, recurrent seizures skeletal muscles consciousness, sensation, vision, smell, etc) due to abnormal neuronal discharge. A single seizure doesn’t mean epilepsy Symptoms Site Size Mechanisms of action of Antiepileptic: At the cellular level, three basic mechanisms are believed to contribute to the antiepileptic action of the currently marketed anticonvulsants.  Modulation of voltage-gated ion channels (Na+, Ca2+, and K+).  Enhancement of γ-aminobutyric acid (GABA)-mediated inhibitory neurotransmission.  Attenuation of excitatory (particularly glutamate-mediated) neurotransmission in the brain (NMDA and AMPA) receptors. Many of AEDs, especially the newer drugs, work by more than one of the above mechanisms of actions, therefore possessing a broader spectrum of antiepileptic action. Voltage-Gated Ion Channels as Targets for Anticonvulsants  VOLTAGE-GATED SODIUM CHANNELS: These aromatic AEDs inhibit excessive neuronal firing by binding to a site near the inactivation gate, thereby prolonging inactivation of VGSCs. Ex. phenytoin, CBZ, and lamotrigine, OXC, felbamate (FBM), and zonisamide.  VOLTAGE-GATED CALCIUM CHANNELS: L-type Ca2 channels in the presynaptic glutaminergic receptors are the primary molecular targets of gabapentin and pregabalin, both of which are effective in refractory partial seizures. T-type Ca2 channels are the molecular targets of ethosuximide and zonisamide.  VOLTAGE-GATED POTASSIUM CHANNELS: Potentiation of the voltage-gated K channels is another attractive target for designing of newer AEDs, because they are intimately associated with the membrane repolarization processes. Ex. Levetiracetam (LEV). GABAA Receptors as Targets for Anticonvulsants:  Drugs that enhance the biosynthesis of GABA (gabapentin, pregabalin and VPA).  Drugs that inhibit GABA degradation (vigabatrin and VPA).  Drugs that inhibit the reuptake of GABA (tiagabine).  Drugs that bind to an allosteric site on the postsynaptic GABA A receptor complex that increase chloride conductance (barbiturates, BZDs) gabapentin, pregabalin CO2 H COOH H2N COOH H2N COOH GAD, Vitamin B6 GABA L-Glutamic acid (Inhibitory NT in brain) (Excitatory NT in brain) COOH O COOH Vigabatrin GABA-T a-Ketoglutaric acid Vitamin B6 (co-substrate) Valproic acid ? TCA cycle H OH SSADH HO COOH O COOH O COOH 4-Hydroxybutyric acid Succinic acid Succinic acid semialdehyde (SSA) Valproic acid Valproic acid Biosynthesis and Metabolism of GABA Excitatory Glutamate-Mediated Receptors as Target for Anticonvulsants  The ligand-gated glutamate receptors such as N-methyl-D-aspartic acid (NMDA)/-amino-3- hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA) receptors.  Modulate sodium and calcium influx and are involved in mediating excitatory synaptic transmission including the initiation and spread of seizure activity.  TPM, deriving some of its antiepileptic action by modulating the AMPA receptor  FBM, which appears to bind to the glycine binding site on the NMDA receptor  Clinically important anticonvulsants 1. Valproic Acid: (Depakote, Depakene)  VPA is a simple chemical structure with broad spectrum of action, but its use is limited by two rare but significant toxic side effects (hepatotoxicity and teratogenicity). These drawbacks are shared by its equipotent active metabolite, (E)-2-propyl-2-pentenoic acid (2-ene- VPA).  Mechanism of action Inhibits GAPA transaminase. Blocks Na channels VGSC. Blocks Ca channels. COOH COOH Valproic acid (VPA) 2-ene-VPA Active metabolite  Valrocemide (valproyl glycinamide, VLR) and DPVPA (SPD-421) are two novel VPA analogs currently in phase II clinical trials.  The anticonvulsant properties of VLR were found to be a result of the parent molecule and not of its metabolic biotransformation to VPA or glycine.  SPD-421, is a phosphatidylcholine derivative of VPA. The phospholipid part of the molecule significantly increases its lipid solubility and facilitates its transport into the brain. However, upon entry into the brain, it is specifically cleaved by the enzyme, phospholipase A2 (PLA2), at the site of seizure to release VPA.  SPD-421 was found to be minimally metabolized in the liver with most of the drug renally eliminated. (there is evidence that the activity of PLA 2 is significantly increased in neurons associated with epileptiform C17H35 activity prior to seizure attack). O CH(C3H7)2 O O O H O N NH2 O O O P O DP-VPA(SPD-421) Valrocemide O CH2CH2N(CH3)3  2. Phenytoin: (Dilantin) and Fosphenytoin: (Cerebyx)  Phenytoin, 5,5-diphenylhydantoin, is a prime example of an effective anticonvulsant acting through its action at the VGSC.  It is structurally very similar to phenobarbital but lacks the dependence liability.  It is very effective against all seizure types except absence seizures.  The drug may be incompletely or erratically absorbed from sites of administration because of its very low water solubility.  fosphenytoin, a prodrug of phenytoin, was developed and marketed to avoid complications such as vein irritation, tissue damage, and muscle necrosis associated with parenteral phenytoin administration.  Fosphenytoin is rapidly absorbed either by intravenous or intramuscular administration. O O O O Phosphatase O P O N HO N HN O NH NH NH O O O Fosphenytoin Phenytoin (Prodrug)  3. Phenobarbital: (Luminal)  Although sedative–hypnotic barbiturates have anticonvulsant properties, only phenobarbital displays enough anticonvulsant selectivity for use as antiepileptics (structure as before). 4. Carbamazepine: (Tegretol) and Oxcarbazepine: (Trileptal)  CBZ, is an iminostilbene derivative of tricyclic antidepressants.  The two phenyls substituted on the urea nitrogen fit the pharmacophore pattern suggested for binding to the VGSC.  Like phenytoin, CBZ is useful in generalized tonic–clonic and partial seizures.  OXC is a newer AED with a similar mechanism of action to CBZ except for its metabolic inactivation pathway.  It is also not a liver enzyme inducer like CBZ and phenytoin. Thus, OXC is said to have much N O NH2 fewer hepatic and idiosyncratic side effects associated with CBZ. Carbamazepine (CBZ)  O HO OH Epoxide CYP3A4 hydrolase N N N O NH2 O NH2 O NH2 Carbamazepine (CBZ) 10,11-CBZ Epoxide 10,11-CBZ diol (reactive metabolite) (Inactive metabolite) O H HO alcohol dehydrogenase N N O NH2 O NH2 Oxcarbazepine (CBZ) (S)-CBZ-10-ol (active metabolite) Metabolism of carbamazepine and oxcarbazepine  5. Gabapentin: (Neurontin) and Pregabalin: (Lyrica)  Gabapentin and its closely related analog pregabalin, (S)-3-isobutyl-GABA, are broad-spectrum anticonvulsants with multiple mechanisms of action.  In addition to modulating calcium influx and stimulate GABA biosynthesis, they also compete for the biosynthesis of L-glutamic acid because of their structural similarity to L-leucine.  More than 95% of the drug is excreted unchanged through the kidneys.  Gabapentin exhibits 60% bioavailability when given in low doses because of intestinal uptake by a saturable small neutral L-amino acid transporter, while the absorption of pregabalin is almost complete (98%).  This high bioavailability of pregabalin can be attributed to its closer structure similarity to the essential amino acid, L-leucine. H2N COOH H2N COOH H2N COOH H H Gabapentin Pregabalin L-Leucine  6. Felbamate: (Felbatol) and Flurofelbamate:  FBM, with a broad spectrum of action, is a carbamate ester which is stable to esterases and therefore provides good oral bioavailability.  FBM therapy was found to be associated with rare but severe side effects such as aplastic anemia, idiosyncratic reactions, and hepatic failures within 6 months of its market introduction.  Extensive clinical metabolic studies with FBM have been able to link the formation of reactive metabolite(s) and the clinically observed toxicities.  Placement of a fluorine atom at the C-2 position of FBM resulted in a very potent anticonvulsant, 2-fluorofelbamate that lacks the idiosyncratic properties of FBM. It is currently under phase II clinical trials. C-2, Benzylic carbon OCONH2 OCONH2 OCONH2 F OCONH2 Felbamate (FBM) 2-fluorofelbamate  Thank You