Anticonvulsant Drugs PDF

Anticonvulsants  Seizure classification  I. Partial Seizures( focal or local seizures)  A. Simple partial seizures  B. Complex partial seizures  C. Partial seizures secondarily generalized  II. Generalized seizures  A. Absence  1. Typical Absence seizures  2....

Anticonvulsants  Seizure classification  I. Partial Seizures( focal or local seizures)  A. Simple partial seizures  B. Complex partial seizures  C. Partial seizures secondarily generalized  II. Generalized seizures  A. Absence  1. Typical Absence seizures  2. Atypical absence seizures  B. Myoclonic seizures  C. Clonic seizures  D. Tonic seizures  E. Atonic seizure  F. Tonic-clonic( grand mal) seizures Seizure classification  I. Partial Seizures( focal or local seizures)  A. Simple partial seizures (Symptoms depend on where the foci is.)  The Temporal lobe is the most common origination site which causes psychic symptoms such as fear, panic or hallucinations; autonomic symptoms such as flushing, sweating and unpleasant tastes or smells.  Frontal lobe foci presents as motor symptoms which starts in one hand or foot or side of the face and spreads to contiguous areas which repeats called a epileptic march. Termed a Jacksonian motor seizure Seizure classification  I. Partial Seizures( focal or local seizures)  A. Simple partial seizures(continued)  Parietal lobe seizures are termed Jacksonian sensory seizures, altered sensations such as tingling, numbness or pain  Occipital lobe seizures lead to nystagmus, blinking or visual disturbances ( flashing lights or the appearance of strange colors  Consciousness is not impaired Seizure classification  I. Partial Seizures( focal or local seizures)  B. Complex partial seizures  Impaired consciousness. The person will stare and does not respond to commands and has inaccurate recall or amnesia of the events during the seizure  C. Partial seizures that progress to generalized seizures Seizure classification  II. Generalized seizures(both hemispheres involved)  A. Absence (petite mal)  1. Typical Absence seizures  Rapid onset and cessation may be misinterpreted as daydreaming but patient can not be awakened. Begins with a change of facial expression progressing to a motionless blank stare after about 10 sec. Goes back to normal with no memory of the events during the seizure and no confusion. More common in children than adults. Tends to occur several times during the day. Seizure classification  II. Generalized seizures(both hemispheres involved)  A. Absence (petite mal)  2. Atypical absence seizures  Attacks with slower onset and cessation lasts several minutes may include clonic motions, automatism and autonomic symptoms Seizure classification  II. Generalized seizures  B.Myoclonic seizures  Sudden brief jerking contractions may involve the whole body or limited to the face and neck. Individual muscle groups are involved with contraction of both extensor and flexor muscles. No loss of consciousness  C.Clonic seizures  Generally seen in babies and young children. Loss of consciousness and decreased muscle tone. Tonic contractions followed by a symmetrical jerking. Seizure classification  II. Generalized seizures  D. Tonic seizures  Increased tone in extensor muscles (Opisthotonos), falling to the ground, loss of consciousness and marked autonomic manifestation.  F. Atonic seizures  Sudden loss of postural tone, with sagging of the head, limb drooping or falling( loss of all muscle tone)  E. Tonic-clonic( grand mal) seizures  Major convulsions usually a sequence of maximal tonic spasm(flexor) of all body musculature followed by synchronous clonic jerking(extensor) and prolonged depression of all central functions. AED’s(anti-epileptic drugs)  A number of different class and individual compounds  Barbiturates- Phenobarbital  Hydantoins- Phenytoin  Oxazolidinediones- Trimethadione  Succinimides- Ethosuximide  Iminostilbenes- carbamazepine  Sulfamate/sulfonamide- Topiramate, Zonisamide  Valproic acid  Gabapentin  Lamotrigine  Levetiracetam  Tiagabine  Felbamate  Benzodiazepines- Clonazepam AED’s(anti-epileptic drugs)  The mechanisms of action of the AED can be divided into three main categories  Some AED act to some extent in all three and some act only in one.  1. Interaction with sodium channels  2. Interaction with GABA receptors( a inhibitory neurotransmitter ) or increasing the amount of GABA available  3. Interaction with T-type Calcium channels AED’s(anti-epileptic drugs)  1. Interaction with sodium channels  The compounds bind voltage dependant sodium channels ( inside the cell) like local anesthetics. This stabilizes of sodium channels in the inactive( refractory state) This decreases the rate of firing and stops the spread of the abnormal action potential which would lead to a seizure.  Phenytoin, carbamazepine,oxacarbazepine and lamotrigine work via this mechanism  Valproic acid, phenobarbital,topiramate and zonisamide may gain some of their effect via this mechanism AED’s(anti-epileptic drugs)  2. Interaction with the GABA receptor  GABA is a inhibitory neurotransmitter. The receptor is a Ligand gated ion channel which allows Chloride to enter the cell. This causes an decrease in the resting potential ( more negative) which make it more difficult to depolarize.  There are allosteric site which allow the GABA to work better ( benzodiazepine sites and phenobarbital? Site)  Other drugs may increase the availability of GABA by increasing the synthesis, decreasing the breakdown, enhancing the release or inhibiting the reuptake  Related to GABA is NMDA(N-methyl D-aspartate) and AMPA(amino-3-hydroxy-5 methyl-4-isoxazole propionate) which are excitatory neurotransmitter. Some compounds block these receptors AED’s(anti-epileptic drugs)  3. Interaction with T-type Calcium channels  T-type calcium channels are pacemaker cell for the CNS in particular in the thalamic region of the brain. This is where absence seizure are thought to originate ( generally via a spike in activity)  The drugs useful in absence seizure all interact with these calcium channel and slow the influx of Calcium into the cell.  Ethosuximide, the oxazolidinediones, zonisamide all interact with Ca channels AED’s  All of the above compounds are imide derivatives. Hydantoins, oxazolidinediones and succinimides are all ring contraction derivative of barbiturates.  Barbiturates and hydantoins are used for partial and generalized seizures whereas the oxazolidinediones and succinimides are only effective for absence seizures AED’s  In the barbiturates and hydantoins, one or both of the R group should be an aromatic ring.  In the oxazolidinediones and succinimides R is generally small alkyl groups (methyl, ethyl). Aromatic rings tend to decrease the activity of the compounds AED’s  Phenobarbital  Weak acid pKa 7.4, 50% unionized good CNS penetration  Absorption is slow but complete  40-60% protein bound  25% excreted unchanged in the urine the remaining is metabolism to the para OH derivative and glucuronidated  2C9 is the major metabolizing enzyme  Half-life:100 hr  It is an inducer of 3A4 and glucuronyl transferease AED’s  Phenobarbital  Phenobarbital is relatively non-selective in its anticonvulsant activity. It limits the spread of seizure activity and also elevates the seizure threshold thus decreasing the number of possible seizures  ADR: sedation is the most common, tolerance develops. Nystagmus and ataxia can occur at excessive doses Hyperactivity and irritability are sometimes seen in children and agitation and confusion in the elderly AED’s  Mephobarbital N-Methyl Phenobarbital  Basically a prodrug of Phenobarbital it is converted by demethylation in the liver.  It is less well absorbed than Phenobarbital  ADR are the same as phenobarbital  AED’s  Primidone (2-deoxy phenobarbital)  Effective for all seizure types except absence  The drug itself is active and it is also converted to two active metabolites Phenobarbital and phenyl ethyl malonamide (PEMA) which accumulate during long term therapy  Some patients may experience an acute feeling of intoxication following administration  Sedation, vertigo and dizziness may also occur  AED’s  Primidone (2-deoxy phenobarbital)  Phenytoin has been reported to increase the conversion to phenobarbital  Used in combination with phenytoin or carbamazepine  AED’s  Phenytoin  Effective for all seizure type except absence  Does not tend to cause CNS depression like phenobarbital  Weak acid pKa 8.3 not very water soluble as free acid  Capsule and Injectable form(pH-10-12) are formulated as sodium salt  Absorption is slow and variable  90% protein bound  AED’s  Phenytoin  Metabolized by 2C9 and 2C19 inducer and inhibitor of both also induces 3A4  The p-hydroxy is the major metabolite which is inactive  5% excreted unchanged in the urine  Undergoes dose dependent kinetics as the dose increases the half-life increases. The plasma concentration does not increase in a dose dependent manner. You can go from sub- therapeutic to toxic with small increases in dose  AED’s  Phenytoin  ADR: acute overdose: nystagmus, ataxia, double vision and vertigo.  Chronic therapy:  CNS Effects hyperactivity, confusion, drowsiness, hallucinations  Gingival hyperplasia  Osteomalacia( alter Vit D metabolism and inhibition of Ca++ absorption)  Hirsutism in young females  AED’s  Fosphenytoin  Water soluble pro-drug of phenytoin for IV use.  Convert to phenytoin by phosphatase in the liver and red blood cells  AED’s  Trimethadione (oxazolidinedione)  Once agent of choice for Absence seizures (introduced 1946)  Mechanism seems to involve interaction with T-type Ca channels  Lead compound for the succinimides which are the DOC for absence 10 y)  Rapid absorption  90% protein bound  Metabolized by conversion to glucuronide also undergoes beta and omega oxidation  ADR: N and V and Anorexia, sedation, ataxia and tremors  AED’s  Valproic acid  Induces 2C9 ( phenytoin and phenobarbital both metabolized by this) also induces Glucuronyl transferase  It should not be used in young children < 2 y. Glucuronidation is not fully developed and oxidative metabolites can cause hepatotoxicity.  AED’s  Carbamazepine( Iminostilbene, dibenzoazepine)  Used since the 60’s for trigeminal neuralgia approved as a AED in 1974  First line drug in combination with other agents for partial seizure and tonic-clonic generalized seizures  The carbamoyl group(technically a urea) is essential for activity  Converted to an active metabolite 10,11 epoxide(next slide) which is further converted to the 10,11 diol which is inactive. The diol is glucuronidated and excreted  AED’s  Carbamazepine( Iminostilbene, dibenzoazepine)  The parent and the epoxide seem to act though modulation of sodium channels like phenytoin  ADR: Acute: stupor and coma, hyperactivity, convulsions and respiratory depression  Long term ADR: drowsiness, vertigo, double vision, blurred vision. Can cause aplastic anemia and agranulocytosis  AED’s  Carbamazepine( Iminostilbene, dibenzoazepine)  Metabolized by 1A2, 2C9 and 3A4  Inducer of 2C9 and 3A4 and glucuronyl transferase  AED’s  Oxcarbazepine  Analogue of carbamazepine  Functions as a prodrug and is immediately converted on absorption to the 10-OH compound which undergoes conjugation  Mechanism is similar to carbamazepine  Less potent inducer that carbamazepine  Useful in partial seizures alone or in combination  AED’s  Eslicarbazepine Acetate Aptiom®  Acetate prodrug of the active of previous compound  The acetate protect the compound from undergoing glucuronidation on first pass  AED’s  Gabapentin  A GABA analogue. The cyclohexane ring increases lipophilicity of the compound  Absorbed by active transport (L-amino acid transporter) in the intestinal tract. This is saturatable, as dose increases the bioavailability goes down. Antacids also decrease absorption  Transported into the CNS by same transporter  No metabolism, excreted unchanged in the urine  AED’s  Gabapentin  Although designed as a GABA analogue it does not mimic GABA at the receptor, it seems to promote GABA release. It also interacts with voltage gated Ca channels which regulate the release of glutamate.  Use: Partial seizure with and without generalization also indicated for post-herpetic neuralgia.  Unlabeled use: diabetic neuropathy, chronic pain, migraine, bipolar disorder, social phobia.  ADR: Sedation, fatigue, ataxia, headaches, dizziness  AED’s  Gabapentin  Other formulations and forms  Gralise® Slow release formulation for Post herpetic neuralgia  Horizant® Gabapentin enacarbril  For Rest Leg Syndrome and Post herpetic neuralgia  Prodrug of gabapentin not effected by transporter saturation  Show dose dependent absorption from 300 mg to 6000 mg  AED’s  Vigabatrin, Sabril®  Mechanism based inhibitor of GABA transaminase, which results in increase levels of GABA  Used as adjunct for Partial complex seizure in ≥ 10 y.o. and infantile spasms 1 month to 2 years  No metabolism and no protein binding, eliminated unchanged in the urine AED’s Vigabatrin mechanism  AED’s  Pregabalin Lyrica® (C-V)  Another GABA analogue it too does not mimic GABA at the receptor. It seems to interact with the voltage gated Ca channels that regulate glutamate release  >90% bioavailable does not seem to undergo active transport in GI(this is based on the absorption not being saturatable  No protein binding  Active transport into the CNS via L amino acid transporter  Excreted unchanged in urine  AED’s  Pregabalin Lyrica® (C-V)  Use: Adjunct in partial seizures, diabetic neuropathy, post- herpetic neuralgia, Management of Fibromyalgia  ADR: Dizziness, drowsiness, blurred vision, weight gain, peripheral edema.  It has been shown to have some abuse potential, Euphoria reported at doses of 450 mg. In experienced abusers it was rated” good drug effect”, “high”, “liked”  AED’s  Lamotrigine  Originally designed as an anti-folate(DHFR inhibitor) based on the false hypothesis that reducing folate levels would reduce seizure frequency. See next slide for similarity to other DHFR inhibitors  Reduces sustained repetitive firing by stabilizing inactive sodium channels( increases the refractory period similar to phenytoin and carbamazepine)  It also seems to inhibits glutamate release AED’s  AED’s  Lamotrigine  Good oral absorption  Metabolized by glucuronidation: phenytoin and carbamazepine will decrease blood levels due to induction. Valproic acid increases levels due to competition for glucuronide formation. Lamotrigine will increase the levels of the 10,11 epoxide of carbamazepine leading to toxicity  Use: partial and generalized seizures usually in combination with other agents  AED’s  Lamotrigine  ADR: Dizziness, ataxia, blurred and double vision, N+V, and rash  Rash is more common in children, increase incidence with Valproic acid. A few cases of Steven-Johnson’s syndrome have been reported.  Lamotrigine may be confused with labetalol, Lamisil®, lamivudine, Lomotil®, ludiomil  Lamictal® may be confused with Lamisil®, Lomotil®, ludiomil  AED’s  Levetiracetam  Structurally unrelated to other AED’s  The exact mechanism is unknown, It has been shown to bind to the synaptic vesicle protein 2A which enhances GABA release from storage vesicles  Good oral absorption  No protein binding  65% unchanged in urine,  No CP450 interaction, minor metabolite is the acid  AED’s  Levetiracetam  Use: refractory partial seizures as an add-on  ADR: generally well tolerated drowsiness and dizziness reported  Increased incidence of psychosis noted in clinical trials  AED’s  Tiagabine  A derivative of nipecotic acid which is a GABA reuptake inhibitor  Tiagabine blocks the GAT1 ( GABA transporter) increasing GABA at the receptor  Well absorbed 90-95% bioavailable  Highly protein bound(95%)  Metabolized by 3A4 and glucuronidation Not an inhibitor or inducer  AED’s  Tiagabine  Use: add-on for refractory partial seizures  ADR: Drowsiness, headache, dizziness, tremor, abnormal thinking, depression, Psychosis  It has induced absence status epilepticus. Contra-indicated in absence seizures  AED’s  Topiramate  Sulfamate of a fructose derivative  Interacts with sodium channels and reduces repetitive firing by increasing refractory period, enhances GABA mediated chloride flux, antagonist at the AMPA receptor and inhibits Ca t-type channels  80-95% bioavailable  Low protein binding  20-30 half-life, inducers decrease half-life  Induces 3A4 and inhibits 2C19  AED’s  Topiramate  Use: single agent for partial and generalized and refractory partial and generalized tonic-clonic  ADR: Drowiness, dizziness, impaired concentration, memory, speech and language difficulties, confusion,  Increased incidence of renal stones( contra-indicated in family history of stones)  Weight loss(has a unlabeled use)  Change the taste of carbonated beverages  Inhibitor of Carbonic anhydrase  AED’s  Felbamate  A dicarbamate derivative related to meprobamate and carisoprodol  Approved in 1993 but due to several cases of aplastic anemia and severe hepatotoxicity a black box warning was added  It is reserved for severe refractory seizures  It seems to be an antagonist at the NMDA receptor  Metabolism of felbamate leading to toxicity  AED’s  Felbamate  Scheme previous slide shows the metabolism  Esterase cleaves one carbamate to give the alcohol. Which is oxidized to the aldehyde and then to the carboxylic acid. The aldehyde can undergo spontaneous elimination of the carbamoyl group forming phenylpropenal which can cause liver damage and other toxicities. It is detoxified by glutathione. As with acetaminophen once glutathione runs out damage begins to occur  AED’s  Zonisamide  A sulfonamide derivative  Blocks both sodium channels and t-type Ca channels  Slow absorption  50% protein bound  N-acetylated, 3A4 and 2D6 involved  AED’s  Zonisamide  Use: partial seizures not controlled by first line agents  ADR; Drowsiness, anorexia, dizziness, agitation, confusion, cognitive impairment, memory loss, increased incidence of psychosis  Renal stone formation (1%) increased in family history  Carbonic anhydrase activity  Recommended to D/C drug if rash develops due to the chance of Steven-Johnson syndrome