CNS Disorders Flashcards
Classification of Seizures
Generalized Seizures: Tonic-Clonic (Grand Mal) Absence Seizures (Petit Mal) Partial Seizures: Complex-Partial (Psychomotor) Simple Partial (Jacksonian) Other myoclonic, atonic
Tonic-Clonic Seizure Components
Aura
Tonic
Clonic
Intra-ictal
Mechanism of Anticonvulsants
Prolong sodium channel inactivation (Most agents), Calcium channel blockade (T&R types, Absence agents), “Cav alpha-2-delta” channel (Reduces neuropathic pain), GABA receptor activity (A for Tonic-Clonic, B for Absence seizures and GABA prolongation), Blockade of Glutamate receptors NMDA, non-NMDA; Other SV2 Synaptic protein (Levatiracetam), K+ channel activation, GAT, CRMP-2 (Lacosamide)
Antiepileptic Drug Resistance
P450 - Induction of hepatic oxidative enzymes
UGT - Induce synthetic UGT pathways
P Glycoprotein Efflux Pumps - Induce ABC proteins-efflux proteins, Multiple Drug Resistance Proteins (MDR1=P-Glycoprotein; Glutamate increases resistance and COX2 inhibitors); Inhibitors of ABC improve drugs in patients
Hydantoins
Ex. Phenytoin (Dilantin), T200, Mephenytoin, Ethotoin; Fosphenytoin (Cerebyx - IV, IM);
Emergency IV or IM
Fosphenytoin - Dephosphorylated by blood phosphatases
Phenytoin
Derived from Barbiturate
Basic pKa (10) - GI Upset
Capsule excipiants alter rate of absorption - Lactose (Immediate release), Calcium Carbonate (Delayed release)
Primary metabolism - CYP2C9 and 2C19; Metabolism saturable (non-linear) at effective concentration - Increasing dose or blocking metabolism produces disproportionate effect or toxicity; Induces drug metabolism
Effect - 1st order then 0 order
Hydantoin Pharmacology
Prolong sodium channel inactivation, Decreases rapid neuron firing
Blocks seizure spread, But NOT focus
Treat tonic-clonic seizures and minor indication in neuralgia and arrhythmia
Hydantoin Adverse Effects
Gingival overgrowth (Dental hygiene and plaque control)
Cardiac - Contraindicated in bradycardia, SA block, 2nd or 3rd degree AV block, Adams-Stokes syndrome, BB warning, Liver enzyme induction (Metabolism of other drugs induces P450);
Skin eruption, GI distress, peripheral neuropathy, hirsutism, hepatitis, nystagmus, bone marrow depression, systemic lupus erythematosus, Stevens-Johnson syndrome and lymphadenopathy
Teratogenic - Palette, Lip
Drug-Induced Gingival Overgrowth (GO)
Children, OH will reduce, Teeth/Prosthetic teeth increase (Rare in edentulous)
Phenytoin, Cyclosporine A, Calcium Channel Blockers (Dihydropyridines)
Drug-Induced Gingival Overgrowth - Folate
Increase Folic acid - Decreases anticonvulsant effect of Phenytoin
Increase Phenytoin - Clearance of Folic acid
Use least vitamin necessary (1mg)
Cause of increased Bleeding
Phenytoin - Reduces Vitamin K and D
Hydantion Drug Interactions
Antacids decrease anticonvulsant solubility; Induces CYP2B6, CYP3A4, substrate for 2C9 and 2C19, Multidrug resistance inducers; Other drugs increase Hydantoin blood levels - Cimetadine, Miconazole, Benzodiazepine, Salicylate, Alcohol, Ibuprofen, Metronidazole; Plasma protein binding drug interactions; Other drugs decrease Hydantoin effects - Barbiturates, Anticonvulsants, Alcohol, Antiacids, Folic acid; Phenytoin decreases APAP, Corticosteroids, Estrogens, Anticonvulsants, Haloperidol, Levo-dopa; Blood levels of folic acid and anticonvulsants reduced
Carbamazepine (Tegretol)
Ex. - Cabamazepine, Oxcarbazepine T200, Trileptal, Eslicarbazine, Stedesa
Chemistry - Classified as iminostilbene, structure like antidepressant, Chronic half-life of 10-20hrs
Mechanism of action - Prolong sodium inactivation, Inhibits uptake and release of NE nerves, Modulates adenosine binding sites
Carbamazepine Use
Partial seizures, Generalized seizures, Neuropathic pain (Neuralgia), Mood (Bipolar depressive disorder, Failure of impulse control)
Carbamazepine Toxicity
Sedation, Headache, Ataxia, Diplopia, GI side effects
Acute Overdose - Stupor, Coma, Convulsion, Hyper-Irritability and Respiratory depression
Chronic - Hematological toxicity (BB), Agranulocytosis, Leukopenia, Neutropenia, Thrombocytopenia; Contraindicated in bone marrow depression, Vertigo, Drowsiness, Blurred vision, Hepatotoxicity, Mood changes, Alopecia, Impotence
Asian Patients - Black box
Contraindicated in allergies or porphyria
Carbamazepine Drug Interactions
Erythromycin, Propoxyphene (Darvon), Block CBZ metabolism; Phenobarbital, Phenytoin and Valporate increase metabolism of Carbamazepine; Induces hepatic metabolizing enzymes; Monoamine Oxidase inhibitors
Valproic Acid
Depakene, Depakote, Depacon IV, T200
Simple Branched Carboxylic acid - pka=4.7; Complex pharmacokinetics
Blocks sodium channels, GABA receptors, T Ca++ channels, Histone deacetylase inhibitor
Valproate Uses
Tonic-Clonic seizures (Broad spectrum agent) and Status Epilepticus
Absence seizures
Mania in bipolar disorder
Migraine
Non FDA Approved - Agitation, Dementia, Hiccups
Valproic Acid Adverse Reactions
Drowsiness, Alopecia (Hair loss), Bleeding (Decreased platelet aggregation, Coagulopathy, Thrombocytopenia), Hepatotoxicity (Fatal; Black box for neonate, infants and children; Contraindicated in hepatitis); Pancreatitis (Fatal BB), Teratogenicity
Valproate Drug Interactions
Other sedative increase sedation, Erythromycin and Cimetadine increase blood levels, Phenobarbital, Phenytoin and Carbamazepine affected; Warfarin, Zidovudine, Tolbutamide
Barbiturates
Phenobarbital, Mephobarbital, Methabarrbital, Primidone
Phenobarbital pKa about 7.4 (Sodium slats basic), Renal excretion sensitive to urinary pH, T1/2 100hrs slow to steady state
Barbiturate Pharmacology
Anticonvulsant - Blocks epileptic Focus AND Spread of seizure, Used for tonic-clonic seizures, Complex partial seizures and Status epileptics
Barbiturate Adverse Effects
Sedation, Dependence, Respiratory Depression, GI, Metabolic Enzyme Induction (Induces PBREM, Impacts drugs and vitamins, Exacerbate acute intermittent porphyria, Avoid in hepatic disease), Birth defects and Barbiturate hypersensitivity
Absence Seizures
Spike-dome EEG, Patient is unconscious but posture maintained with minimal motor signs, Seizures thought to be in thalamus, Seen more in children, May have hundreds of daily seizures
Ethosuximide (Zarontin)
Chemsitry - Succimides, Several available Ethosuximide (Least toxic), Methsuximide, Phenensuximide
Effective for Tx of absence seizures, Molecular action on T Ca++ channels, Will block pentylenetetrazole induced seizures but not electro-induced seizures, Not effective for tonic-clonic seizures
Ethosuximide Toxicity
GI disturbances, CNS drowsiness, lethargy and euphoria; Skin-Urticaria, Stevens-Johnson (Rare), Lupus erythematosus (Rare), Aplastic anemia (Rare)
Pregabalin (Lyrica)
Gabapentin and Pregabalin are being used more than Carbamazepine;
Increase GABA levels, Increased GAD (Glutamic Acid Decarboxylase) and binds alpha-2-delta subunit of Ca channels, 3 to 10 more potent than Gabapentin (Neurontin)
Pregabalin Use and Adverse Reactions
Primarily used for neuropathic pain (Diabetic neuropathy, Fibromyaglia, Postherpetic neuralgia) but also seizures and anxiety, Reduces post operative pain
Adverse Reactions of swelling, sleepiness, dizziness, blurred vision, weight gain, suicidality, Withdrawal reaction may occur
Pregabalin Drug Interactions
Antidiabetic agents, ACE inhibitors, Opiates and Benzodiazepines
