Antiseizure Drugs BY DR IRIBHOGBE OI [Autosaved].pptx

ANTISEIZURE DRUGS BY IRIBHOGBE O.I. (ASS. PROF) MBBS, MPH, PHD, CERT. CLIN. PHARM, MISPE `  HIGHLIGHTS Introduction Classification of Seizures & Antiseizure Drugs Mechanisms of Action of Antiseizure Drugs Pharmacology of Specific Agents...

ANTISEIZURE DRUGS BY IRIBHOGBE O.I. (ASS. PROF) MBBS, MPH, PHD, CERT. CLIN. PHARM, MISPE `  HIGHLIGHTS Introduction Classification of Seizures & Antiseizure Drugs Mechanisms of Action of Antiseizure Drugs Pharmacology of Specific Agents & their Clinical Uses Summary/Conclusion  INTRODUCTION Seizure is a neurological condition characterized by abnormal rhythmic firing of cerebral neurons A chronic CNS disorder characterized by repetitive episodes of seizure is known as epilepsy  CLASSIFICATION OF SEIZURES & ANTIEPILEPTIC DRUGS Seizure disorders are classified into: Partial and Generalized seizures Partial seizures: Simple partial seizures Complex partial seizures Partial seizures that are secondarily generalized  CONTD Generalized Seizures: Tonic-clonic (Grand Mal) seizures Absence seizures (Petit Mal) Tonic seizures Atonic seizures Clonic & Myoclonic seizures Infantile spasm  CLASSIFICATION OF ANTISEIZURE DRUGS Generally they have a heterocyclic ring structure with different substituents attached to the heterocyclic ring This determines the chemical group of the drugs They are classified into the following chemical groups: FIGURE 1: HETEROCYCLIC RING OF ANTIEPILEPTIC DRUGS FIGURE 2: STRUCTURES OF ANTIEPILEPTIC DRUGS  CONTD Acetyl ureas e.g. phenacemide Barbiturates e.g. phenobarbitone, primidone, mephobarbitone Benzodiazepines e.g. clonazepam, diazepam Hydantoins e.g. phenytoin, mephenytoin Oxazolidinedione e.g. dimethadione, trimethadione Succinimide e.g. Ethosuximide, phensuximide  CONTD Iminostilbene e.g. carbamazepine Aliphatic carboxylic acid e.g. valproic acid Newer agents e.g. progabide, vigabatrin, gabapentin, lamotrigine, felbamate, topiramate, tiagabine Miscellaneous e.g. acetazolamide, dexamphetamine  MECHANISMS OF ACTION OF ANTISEIZURE DRUGS Inhibition of Na channels: the channel is blocked when the Na gate is opened Thus prolonging the opening of the channel and leaving it in an inactive state The channels become refractory to stimulation Examples of drugs that act via such mechanism are; phenytoin, carbamazepine, valproate, topiramate, lamotrigine FIGURE 3: MECHANISMS OF ACTION OF AEDS  CONTD Increase in inhibitory NT activity in the CNS: This occurs following binding to GABAA -BZD-Cl channel complex ↑ GABAmimetic & GABA facilitatory action in the CNS Examples of drugs exhibiting this action include; diazepam, clonazepam, phenobarbital e.t.c. FIGURE 3: GABA-BZD-CL CHANNEL COMPLEX FIGURE 4: MOAS OF BAB & BZ  CONTD ↑ in the release of GABA in the neuronal terminal e.g. gabapentin ↓ in the metabolism of GABA at the neuro-effector junction in the CNS e.g. vigabatrine ↓in the reuptake of GABA into the neuronal terminal e.g. tiagabine  CONTD ↓ Excitatory NT activity in the CNS: Major excitatory NT in the CNS are glutamate and Aspartate Glutamate acts by stimulating metabotropic or ionotropic receptors in the CNS Stimulate metabotropic receptor GPCRs, and ionotrophic receptors; kainate, NMDA and AMPA receptors Valproate inhibit excitatory activity at NMDA receptors while topiramate inhibit excitatory activity at kainate receptors  CONTD Inhibition of Ca2+ channels: Acts by inhibiting slow ca2+ (T-type) channels in the thalamic neurons They are oscillatory ion channels implicated in the pathophysiology of absence seizure Drugs that inhibit this channels are useful in the Px of absence seizures e.g. ethosuximide, phensuximide, valproate, lamotrigine FIGURE 5: INHIBITION OF T-TYPE CA CURRENT  PHARMACOLOGY OF SPECIFIC AGENTS & Phenytoin: THEIR CLINICAL USES Chemistry: it is a diphenylhydantoin. The prodrug fosphenytoin is more water-soluble and is administered intravenously or via IM PK: oral absorption depends on the formulation Phenytoin sodium is almost completely absorbed from the gut Achieves peak plasma concentration within 3-10 hrs IM absorption is not predictable since the drug may precipitate in the muscle hence, this route is not usually recommended  CONTD Phenytoin is highly protein bound, and it accumulates in ER of cells in the brain, liver, muscle and adipose tissues It is metabolized in the liver by hydroxylation to parahydroxy-5-phenylhydantoin (HPPH) HPPH is conjugated by glucuronic acid to water soluble products that are excreted via renal route T-half ranges from 12-36 hrs  CONTD MOAs: acts via several mechanisms Inhibits sodium ion conductance across excitable membranes Alters synaptic concentration of inhibitory NT Resulting in either presynaptic or postsynaptic inhibition Interacts directly with membrane lipids thereby promoting the stabilization of excitable membranes  CONTD Clinical Uses: Used in the treatment of; simple partial, complex partial, and generalized tonic- clonic seizures Also used in the treatment of status epilepticus  CONTD Adverse Effects: CNS: at toxic plasma levels diplopia, ataxia, vertigo, nystagmus Gingival hyperplasia, hirsutism, coarsening facial features from chronic use Megaloblastic anemia, vit D deficiency result in in rickets, osteomalacia Vit K deficiency, hyperglycemia, hypersensitivity reactions  CONTD It is teratogenic and can cause cleft lip, cleft palate, and congenital heart diseases Hence is contraindicated in pregnancy It can also cause hematological disorders such as lymphadenopathy and agranulocytosis  CONTD Carbamazepine: Chemistry: it is a heterocyclic compound, similar to phenytoin and possess an ureido moiety (N-CO-NH2) PK: GIT absorption is almost complete in most patients Peak plasma levels are achieved within 6-8hrs Vd 1 kg/L and approx. 70% bound to plasma proteins. T1/2 is 36hrs Completely metabolized in the liver and excreted in urine. The metabolites carbamazepine 10, 11- epoxide have antiseizure activity  CONTD MOAs: Blocks Na ion channel and inhibit high frequency repetitive firing in neurons Potentiate postsynaptic action of GABA thereby interfering with synaptic transmissionInhibits uptake and release of NE from brain synaptosomes  Clinical Uses: Used in the Px of simple partial, complex partial and generalized tonic-clonic seizures Adverse Effects: Stupor, coma, confusion, hyperirritability, and respiratory depression from acute intoxication From long term use can cause CNS effects such as drowsiness, vertigo, blurred vision, diplopia and ataxia  CONTD GIT disturbances such as nausea and vomiting can occur Water intoxication and hyponatremia Hematological abnormalities include aplastic anemia and agranulocytosis  CONTD Ethosuximide: Chemistry: it is a 2-ethyl, 2-methyl succinimide PK: absorption is complete after oral administration. Peak plasma conc. Is achieved within 3-7hrs It is widely distributed in tissues but do not penetrate fatty cells Vd is approx. 0.7kg/L and is not protein bound Completely metabolized by hydroxylation in the liver and excreted in urine. T ½ = 40hrs  CONTD MOAs: It blocks low-threshold T-type ca2+ current in thalamic neurons which are the pacemaker current responsible for the rhythmic cortical discharges in absence seizures It inhibits Na+/K+ ATPase and depress cerebral metabolic rate as well as inhibit GABA aminotransferase  CONTD Clinical Use: It is the drug of choice in the Px of Absence seizure Other drugs that can be used in the Px of absence seizure includes; valproate, phensuximide, dimethadione, and trimethadione  CONTD Adverse Effects: GIT discomfort such as nausea, vomiting, abdominal pain, anorexia CNS effects such as lethargy, fatigue, headache, drowsiness, euphoria and hiccup Hematological abnormalities such as eosinophilia, leucopenia, thrombocytopenia, bone marrow depression Hypersensitivity reactions such as exfoliative dermatitis, Stephen’s Johnson syndrome  CONTD Primidone: Chemistry: it is a barbiturate. It is a 5-ethyl-5-phenyl-,3- diazinane-4,6-dione compound PK: oral bioavailability is complete, 25% protein bound. Time to reach steady state conc is 2-3 days, t-half is 5-8 hrs Metabolized in the liver by cyt P450 enzymes into its active metabolite (one of which is phenobarbitone). It also induces cyt p 450 enzymes. Metabolites are excreted via the kidney  CONTD MOAs: it alters transmembrane Na/Cl transport channel to reduce the frequency of repetitive firing One of its metabolite phenobarbitone interacts with GABAA-Cl channel complex inhibit neuronal excitability Clinical uses: it is used as second line agents in the treatment of essential tremors It is used in the Px of partial and generalized tonic-clonic seizure  CONTD Adverse effects: CNS depression, sedation, dizziness, confusion, fatigue, ataxia, vertigo, diplopia, nystagmus GIT disturbances viz nausea, vomiting, abdominal discomfort Can cause rickets, osteomalacia due to vit D deficiency. Also cause vit B12 and folic acid deficiency  CONTD Hypersensitivity reactions Hematological abnormalities such as; leucopenia, thrombocytopenia, hypoprothrombinemia in newborn whose mothers were treated with primidone Connective tissue disorders such as Lupus  SUMMARY/CONCLUSION Antiseizure drugs acts through various mechanisms which includes: Na channel blockade ↑ inhibitory NT activity ↓excitatory NT activity Inhibition of slow Ca2+ ion current  CONTD Carbamazepine, phenytoin, lamotrigine, phenobarbital are mostly used in partial and generalized tonic-clonic seizures Ethosuximide, valproate, and trimethadione are used in absence seizures Diazepam is DOC in infantile spasm and febrile seizures DOC in status epilepticus includes diazepam, lorazepam, phenytoin and phenobarbital THANK YOU CLASS