Antiepileptic Drugs PDF

Antiepileptic Drugs By Dr. Harshika Patel NRSG 232: Pharmacology II P-Slide 1 KeMU, 2020  Definitions  Epilepsy: These are Group of disorders of the CNS characterized...

Antiepileptic Drugs By Dr. Harshika Patel NRSG 232: Pharmacology II P-Slide 1 KeMU, 2020  Definitions  Epilepsy: These are Group of disorders of the CNS characterized by paroxysmal cerebral dysrhythmia, manifesting as brief episodes (seizure) of loss or disturbance of consciousness, with or without characteristic body movements (convulsions), sensory or psychiatric phenomena Seizure: the clinical manifestation of an abnormal synchronization and excessive excitation of a population of cortical neurons P-Slide 2 Types of seizures P-Slide 3 P-Slide 4 Etiology Idiopathic Children: Birth traumas, infections – meningitis and congenital abnormalities* Middle age: Alcohol, infections, head injury and Drugs like cocaine, low blood sugar, low oxygen, low blood Na+ and low Ca+ etc. Elderly: Stroke, tumors etc. Congenital*  Antiepileptic Drug  A drug which decreases the frequency and/or severity of seizures in people with epilepsy  Treats the symptom of seizures, not the underlying epileptic condition  Goal—maximize quality of life by minimizing seizures and adverse drug effects P-Slide 6 Classification: chemical nature Hydantoins: phenytoin, phosphenytoin Barbiturates: phenobarbitone Iminostilbenes: carbamazepine, oxcarbazepine Succinimides: ethosuximide Aliphatic carboxylic acid: Valproic acid, divalproex Benzodiazepines: clonazepam, diazepam, lorazepam New compounds: gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin, zonisamide, felbamate P-Slide 7 Cellular Mechanisms of Seizure Generation  Excitation (too much) Ionic-inward Na+, Ca++ currents Neurotransmitter: glutamate, aspartate  Inhibition (too little) Ionic-inward CI-, outward K+ currents Neurotransmitter: GABA P-Slide 8  Oxcarbazepine Zonisamide Levetiraceta m Levetiraceta Pregabalin m Pregabalin P-Slide 9 Phenobarbitone First effective organic antiseizure agent Pharmacokinetics: Slowly absorbed and long t1/2 (80 – 120 hrs) Metabolized in liver and excreted unchanged in kidney Single dose after 3 wks. – steady state Adverse effects: Sedation Behavioral abnormalities Hyperactivity in children Rashes, megaloblastic anaemia and osteomalacia P-Slide 10  Contd… Primidone: Deoxybarbiturate Converted to Phenobarbitone and have Short half life 6-14 hrs Uses: Many consider them the drugs of choice for seizures only in infants GTC SP and CPS Dose: 60 mg 1-3 times a day, Child: 3-6 mg/kg/day Available as tabs – 30/60mg, syr. and inj. P-Slide 11  Phenytoin Pharmacological actions: Not CNS depressant But muscular rigidity and excitement at toxic doses Abolish tonic phase of GTC seizure No effect on clonic phase Prevents spread of seizure activity Tonic-clonic epilepsy is suppressed but no change in EEG and aura.. In CVS – depresses ventricular automaticity, accelerates AV conduction P-Slide 12  Contd.. Pharmacokinetics: Slow oral absorption 80-90% bound to plasma protein Metabolized in liver by hydroxylation and glucuronide conjugation Elimination varies with dose T1/2 life is 12 to 24 hrs Cannot metabolize by liver if plasma conc. is above 10 mcg/ml Monitoring of plasma concentration P-Slide 13  Contd.. Adverse effects: Hirsutism, coarsening of facial features and acne Gum hypertrophy and Gingival hyperplasia. Hypersensitivity – rashes, lymphadenopathy Megaloblastic anaemia Osteomalacia Hyperglycemia Cognitive impairment Exacerbates absence seizures Fetal Hydantoin Syndrome P-Slide 14 https://www.brainkart.com/article/Phe nytoin---Anticonvulsant-(Anti-Epileptic )-Drug_31103/ toxicity of phenytoin P-Slide 15 Contd.. Uses: It is the first line antiepileptic for GTCS, no effect in absence seizure Status epilepticus Trigeminal neuralgia – 2nd to Carbamazepine Available as caps/tabs/inj 25 to 100 mg caps and tabs Drug Interactions: Phenytoin and carbamazepine increases each others metabolism Induces microsomal enzyme – steroids, digitoxin etc Phenytoin metabolism inhibition – by warfarin, isoniazid etc. Sucralfate – decreases phenytoin absorption Important points I.V. phenytoin may forms precipitate, so flush tubing by saline (not dextrose) before & after administration. Cause infusion related reactions*. Safe in pregnancy and allowed in nursing population. Check the liver & kidney function tests before treatment. Regularly, monitor the trough level of drug. To minimize GI upset  take drug with food Monitor the diabetics  for signs of hypoglycemia. Oral hygiene to minimize bleeding from the gum. Report any excessive growth of hair.  Carbamazepine (Tegretol/tegrital) Chemically related to imipramine Trigeminal neuralgia Lithium like action – mood stabilizer Resembles phenytoin in pharmacological actions Pharmacokinetics: Poorly water soluble and oral absorption is low 75% bound to plasma protein Metabolized in liver: active 10-11 epoxy carbamazepine Substrate and inducer of CYP3A4 Half life – 20 to 40hrs. Decreases afterwards due to induction Contd.. Adverse effects: Autoinduction of metabolism Nausea, vomiting, diarrhoea and visual disturbances Hypersensitivity – rash, photosensitivity, hepatitis, granulocyte suppression and aplastic anemia ADH action enhancement – hyponatremia and water retention Teratogenicity Exacerbates absence seizures  Contd.. Uses: Complex partial seizure GTCS and SPS Trigeminal and related neuralgias Manic depressive illness and acute mania Interactions: Enzyme inducer – reduce efficacy of OCPs and others Metabolism is induced by – phenobarbitone, phenytoin, valproate Inhibits its metabolism – isoniazid and erythromycin Ethosuximide: tx of absence seizures Toxicity: Gastric distress, including, pain, nausea and vomiting (minimized with food) Hypersensitivity (monitor the drug level in blood frequently) Lethargy and fatigue Headache Hiccups Euphoria Doses: 20-30mg/kg/day Available as syr./caps. Valproic acid Broad spectrum anticonvulsant Effects on chronic experimental seizure and kindling Potent blocker of PTZ seizure Effective in partial, GTCS and absence seizures Adverse effects: Elevated liver enzymes including own – rise in serum transaminase Nausea and vomiting Abdominal pain and heartburn Tremor, hair loss, weight gain Idiosyncratic hepatotoxicity In Girls – polycystic ovarian disease and menstrual irregularities Negative interactions with other antiepileptics Teratogenicity: spina bifida P-Slide 22 Contd… Drug Interactions: Valproate and carbamazepine induce each others metabolism Inhibits phenobarbitone metabolism and increases its plasma level Displaces phenytoin from protein binding sites and thereby decreases its metabolism – phenytoin toxicity P-Slide 23  Gabapentin GABA derivative and can cross BBB Enhances GABA release, but not agonist of GABA-A Pharmacokinetics: Absorbed orally Not metabolized in humans Not bound to plasma proteins and excreted unchanged in urine Half life is 4 to 6 hrs. Not found any important drug interaction Uses: Partial seizures with or without secondary generalization in addition to other drugs 900-1800mg/day is equivalent to 300 mg/day of carbamazepine if used alone Usual starting dose is 300mg/day Adverse effects: somnolence, dizziness, ataxia etc. Lamotrigine Carbamazepine like action profile and modify maximal electroshock seizure (MES) Uses: Partial (simple and complex) and secondarily generalized, absence seizure, myoclonic seizure in young Monotherapy and add on therapy in simple partial and secondarily generalized seizures. Daily dose – 100 to 300 mg Topiramate Sulfamate substituted monosaccharide Broad spectrum antiseizure drug Carbonic anhydrase inhibitor Antiseizure activity against PTZ, ME seizure and partial and secondarily generalized tonic-clonic kindling Multiple actions – Na+ channel, K+ channel, GABAA, AMPA-kainate subtypes of glutamate Pharmacokinetics: Rapidly absorbed orally, 10-20% bound to plasma protein, excreted unchanged in urine Metabolized by hydroxylation, glucoronidation and hydrolysis Reduction in estradiol level Uses: GTCS, SP and CPS as supplement drug in refractory cases P-Slide 26 Diazepam Commonly used as anticonvulsant in a variety of convulsions But, not used for long term – sedation effect Used in emergency control of convulsion – status epilepticus, tetanus, febrile convulsion etc. Usually given 0.2 to 0.5 mg/kg body weight IV followed by repeated doses if required – maximum dose 100 mg/day Rectal diazepam P-Slide 27 Contd… Adverse effects: Long term use of Clonazepam – drowsiness and lethargy – tolerance to antiseizure effects Muscular incoordination and ataxia Hypotonia, dysarthria and dizziness Behavioral abnormalities in children – aggression, hyperactivity, irritability and difficulty in concentration Increased bronchial and salivary secretions Exacerbation of seizures P-Slide 28 Therapeutic uses: Clonazepam in absence seizure and myoclonic seizure in children (1 to 6 months) Dose initial – 1.5mg/day, children – 0.01 to 0.03mg/kg/day Status epilepticus – Diazepam, Lorazepam may be used as alternative P-Slide 29 Acetazolamide It is a sulfonamide derivative, act as an anticonvulsant by inhibition of carbonic anhydrase in the CNS  inc’ CO2 tension  dec’ neuronal conduction Used: in convulsion and as diuretics* Absence of seizure (petit mal), Grand-mal (tonic-clonic) seizure, Glaucoma. The Cytochrome P-450 Enzyme System Inducers Inhibitors phenobarbital erythromycin primidone nifedipine/verapamil phenytoin trimethoprim/sulfa carbamazepine propoxyphene tobacco/cigarettes cimetidine valproate P-Slide 31  Pharmacokinetic Factors in the Elderly  Absorption — little change  Distribution decrease in lean body mass important for highly lipid-soluble drugs fall in albumin leading to higher free fraction  Metabolism — decreased hepatic enzyme content and blood flow  Excretion — decreased renal clearance P-Slide 32  Pharmacokinetic Factors in Pediatrics  Neonate—often lower per kg doses Low protein binding Low metabolic rate  Children—higher, more frequent doses Faster metabolism P-Slide 33  Pharmacokinetics in Pregnancy  Increased volume of distribution  Lower serum albumin  Faster metabolism  Higher dose, but probably less than predicted by total level (measure free level)  Consider more frequent dosing P-Slide 34  Acute, Dose-Related Adverse Effects of AEDs  Neurologic/Psychiatric – most common · Sedation, fatigue · Unsteadiness, incoordination, dizziness · Tremor · Paresthesia · Diplopia, blurred vision · Mental/motor slowing or impairment · Mood or behavioral changes · Changes in libido or sexual function P-Slide 35  cont…  Gastrointestinal (nausea, heartburn)  Mild to moderate laboratory changes ·Hyponatremia (may be asymptomatic) ·Increases in ALT or AST (LFT) ·Leukopenia ·Thrombocytopenia  Weight gain/appetite changes P-Slide 36 Idiosyncratic Adverse Effects of AEDs  Rash, Exfoliation  Signs of potential Stevens-Johnson syndrome  Hepatic Damage · Early symptoms: abdominal pain, vomiting, jaundice · Laboratory monitoring probably not helpful in early detection · Patient education · Fever and mucus membrane involvement P-Slide 37 CONTD’….  Hematologic Damage (marrow aplasia, agranulocytosis) ·Early symptoms: abnormal bleeding, acute onset of fever, symptoms of anemia ·Laboratory monitoring probably not helpful in early detection ·Patient education P-Slide 38 Long-Term Adverse Effects of AEDs  Neurologic: · Neuropathy · Cerebellar syndrome (ataxia)  Endocrine/Metabolic Effects · Vitamin D – Osteomalacia, osteoporosis · Folate – Anemia, teratogenesis · Altered connective tissue metabolism or growth Facial coarsening Hirsutism Gingival hyperplasia P-Slide 39 Drug choices in different epilepsies. Tonic-clonic, myoclonic, and absence seizures: 1st line drug is usually valproate Generalized seizures: Phenytoin and carbamazepine are effective on tonic-clonic seizures but not other types of seizures Absence seizures: Valproate and ethosuximide are equally effective in children, but only valproate protects against the tonic-clonic seizures that sometimes develop Risk of hepatoxicity with valproate—should not be used in children under 2 P-Slide 40 Partial seizure Without generalization Phenytoin and carbamazepine may be slightly more effective With secondary generalization First-line drugs are carbamazepine and phenytoin (equally effective) Valproate, phenobarbital, and primidone are also usually effective Phenytoin and carbamazepine can be used together (but both are enzyme inducers) P-Slide 41 Contd…. Adjunctive (add-on) therapy: newer drugs gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide Phenytoin and carbamazepine failure: Lamotrigine, oxcarbazepine, felbamate approved for monotherapy Refractory partial seizures: Topiramate can be effective P-Slide 42 Thank you ? P-Slide 43