CNS Disorders

Question 1

Classification of Seizures

Answer 1

Generalized Seizures:
Tonic-Clonic (Grand Mal)
Absence Seizures (Petit Mal)
Partial Seizures:
Complex-Partial (Psychomotor)
Simple Partial (Jacksonian)
Other myoclonic, atonic

Question 2

Tonic-Clonic Seizure Components

Answer 2

Aura
Tonic
Clonic
Intra-ictal

Question 3

Mechanism of Anticonvulsants

Answer 3

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)

Question 4

Antiepileptic Drug Resistance

Answer 4

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

Question 5

Hydantoins

Answer 5

Ex. Phenytoin (Dilantin), T200, Mephenytoin, Ethotoin; Fosphenytoin (Cerebyx - IV, IM);

Question 6

Emergency IV or IM

Answer 6

Fosphenytoin - Dephosphorylated by blood phosphatases

Question 7

Phenytoin

Answer 7

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

Question 8

Hydantoin Pharmacology

Answer 8

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

Question 9

Hydantoin Adverse Effects

Answer 9

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

Question 10

Drug-Induced Gingival Overgrowth (GO)

Answer 10

Children, OH will reduce, Teeth/Prosthetic teeth increase (Rare in edentulous)
Phenytoin, Cyclosporine A, Calcium Channel Blockers (Dihydropyridines)

Question 11

Drug-Induced Gingival Overgrowth - Folate

Answer 11

Increase Folic acid - Decreases anticonvulsant effect of Phenytoin
Increase Phenytoin - Clearance of Folic acid
Use least vitamin necessary (1mg)

Question 12

Cause of increased Bleeding

Answer 12

Phenytoin - Reduces Vitamin K and D

Question 13

Hydantion Drug Interactions

Answer 13

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

Question 14

Carbamazepine (Tegretol)

Answer 14

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

Question 15

Carbamazepine Use

Answer 15

Partial seizures, Generalized seizures, Neuropathic pain (Neuralgia), Mood (Bipolar depressive disorder, Failure of impulse control)

Question 16

Carbamazepine Toxicity

Answer 16

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

Question 17

Carbamazepine Drug Interactions

Answer 17

Erythromycin, Propoxyphene (Darvon), Block CBZ metabolism; Phenobarbital, Phenytoin and Valporate increase metabolism of Carbamazepine; Induces hepatic metabolizing enzymes; Monoamine Oxidase inhibitors

Question 18

Valproic Acid

Answer 18

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

Question 19

Valproate Uses

Answer 19

Tonic-Clonic seizures (Broad spectrum agent) and Status Epilepticus
Absence seizures
Mania in bipolar disorder
Migraine
Non FDA Approved - Agitation, Dementia, Hiccups

Question 20

Valproic Acid Adverse Reactions

Answer 20

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

Question 21

Valproate Drug Interactions

Answer 21

Other sedative increase sedation, Erythromycin and Cimetadine increase blood levels, Phenobarbital, Phenytoin and Carbamazepine affected; Warfarin, Zidovudine, Tolbutamide

Question 22

Barbiturates

Answer 22

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

Question 23

Barbiturate Pharmacology

Answer 23

Anticonvulsant - Blocks epileptic Focus AND Spread of seizure, Used for tonic-clonic seizures, Complex partial seizures and Status epileptics

Question 24

Barbiturate Adverse Effects

Answer 24

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

Question 25

Absence Seizures

Answer 25

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

Question 26

Ethosuximide (Zarontin)

Answer 26

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

Question 27

Ethosuximide Toxicity

Answer 27

GI disturbances, CNS drowsiness, lethargy and euphoria; Skin-Urticaria, Stevens-Johnson (Rare), Lupus erythematosus (Rare), Aplastic anemia (Rare)

Question 28

Pregabalin (Lyrica)

Answer 28

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)

Question 29

Pregabalin Use and Adverse Reactions

Answer 29

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

Question 30

Pregabalin Drug Interactions

Answer 30

Antidiabetic agents, ACE inhibitors, Opiates and Benzodiazepines