Exam 1 - Neurology Meds Flashcards
What drugs cause seizures?
Theophylline Alcohol Phenothiazine antipsychotics Antidepressants (Buproprion) AEDs
GABA
Inhibitory neurotransmitter
Glutamate
Excitatory neurotransmitter
What drug causes glutamate to be converted into GABA? Why is this bad?
Glutamate is converted into GABA.
INH: inhibits enzyme that makes GABA > glutamate.
Patients develop seizures from too much glutamate activity.
Toxin Induced Seizures
What causes them?
OTIS CAMPBELL
OTIS CAMPBELL
Oral hypoglycemics and organophosphates Theophilline/TCA Isoniazid/Insulin Salicylates Camphor, cocaine, carbon monoxide Amphetamines, anticholinergics Methylxanthines PCP Ethanol withdrawal Lidocaine/Lead Lindane/Lithium
Phenytoin
- Treats seizures
- Dose depends on age of patient, maturation of liver, and pharmacokinetics
Children 6m-3y metabolize at an increased patient 8-10mg/kg/day, while a 16y can only metabolize 6mg/kg/day.
Treatment options
Anti-epileptic drugs
Surgery to remove hyperactive parts of the brain
Ketogenic diet - puts patient in ketoacidosis. Acidifying blood increases seizure threshold.
Issue for peds - drugs come in suspensions that include sugar to make it taste better. Hard to manage patient on a ketogenic diet; check their food, meds.
AED therapy -
- What do you start with?
- What if you’ve failed multiple drug attempts?
Monotherapy should be tried first; add on additional agents if seizures are not controlled.
When multiple drug attempts are failed, may try nerve stimulator, ketogenic diet, and surgery. Charlotte’s web.
What is the drug of choice for absense seizures?
How does it work?
Ethosuximide
- Blocks T channels (Calcium)
- Only used for absence seizures
- Valproate also works on calcium channels to help limit depolarization of neuron
GABA A receptor
GABA binds to GABA A receptor:
- Opens channel and allows chloride to flow in
- Hyperpolarizes cell to prevent it from firing off
GABA A: Target for seizures
What drug will modulate GAD, which is responsible for metabolizing glutamate into GABA?
Isoniazid
-Increasing glutamate metabolism, produces more GABA to be released and stop APs.
What drug blocks the reuptake of GABA?
Tiagabine
-More GABA in synapse will inhibit neuron from firing off.
What drug inhibits GABA metabolism by turning off the enzyme GABA transaminase?
Vigabatrin
-Stops the metabolism in the neuron to keep GABA there.
What drug allosterically causes GABA to be more effective in enhancing movement of chloride ions through the channels?
Phenoarbital Benzodiazepines -Make GABA work better -Hyperpolarize, calcium influx -Good for status epilepticus and acute seizures
GAD role
Increases amounts of GABA being made
Glutamate receptors
Excitation
- AMPA site
- NMDA site
- Kainate site
What drugs work to block glutamate from binding to receptors?
NMDA: Felbamate and Levetiracetam
AMPA/Kainate: Topiramate
What hormones have seizure inhibiting effects?
Progesterone prevents seizures, while estrogen may cause seizures.
Carbonic anhydrase inhibitors
-Acetazolamide
Drugs increase hydrogen ions intracellularly; makes blood acidic so seizure threshold is increased.
Phenytoin (Dilantin)
- Treats generalized and partial seizures
- Blocks sodium channels, so less firing of APs.
- Protein bound.
- Metabolized by CYP2C9 and CYP219
- Induces CYP3A, 2C, and PGP
- Michealis Menten kinetics put you at risk for toxicity with higher doses (0 order) - hepatocytes are oversaturated.
Phenytoin (Dilantin) ADR
- Lethargy, blurred vision, nystagmus, ataxia, fall risk
- SJS
- Gingival hyperplasia, hirsutism
Why do we prefer Fosphenytoin over Phenytoin?
Phenytoin
- Formulated with alcohol, propylene glycol - hard on the veins!!!
- Can cause purple glove syndrome; tissue starts to become necrotic.
Water soluble form: Fosphenytoin
- SAFER administration
- First line for generalized and partial seizures.
Phenytoin Dosing Levels
- Phenytoin is 90% protein bound.
- Two levels: Free/Total
- Free - in blood
- Total - in blood/bound to proteins
Those with liver problems who don’t produce enough albumin, will have a higher free level.
Breakthrough seizures and increased toxicity – check the free level!
Altered binding:
- Hypoalbuminemia
- Renal failure
- Multi-antiepileptic drug therapy
What happens if you administer over 50mg/min of Phenytoin?
Phlebitis and cardiovascular complications
Fosphenytoin - less pain and phlebitis, can do 150mg/min. Needs to be converted, though.
PE
phenytoin equivalence
Carbamazepine (Tegretol)
- Treats seizures, mood stabilizer, and bipolar disorder
- Sodium channel blocker
- Induces CYP3A4, 2C9, 2C19
Autoinduction: metabolizes itself, dose has to increase over first few weeks until its stable. Otherwise, blood levels will drop
ADR: Bone marrow suppression, thrombocytopenia, leukopenia
SIADH - syndrome of inapropriate antidurietic hormone!!!!!!!!!!!!!!!!!
Oxcarbazepine (Trileptal)
Less enzyme induction, causes more SIADH. Hyponatremia.
Valproic acid (Depakote)
Blocks sodium, calcium chennels and enhances GABA
Used for bipolar and mood stabilizer
High protein binding
Valproic Acid ADR
Sedation, ataxia, tremor
Drug induced pancreatitis
Hepatotoxicity
Valproic Acid DI
Use caution with drugs that inhibit PLT function, can see thrombocytopenia
Inhibit CYP2C9 and UGT (affect iamotrigene, lorazepam)
Benzodiazepines
- Diazepam (Diastat)
- Lorazepam (Ativan)
- Midazolam (Versed)
- Clonazepam (Klonoprin)
- Clobazam (Onfi)
Diazepam - rectal gel (used for acute seizures)
Midazolam - intranasal; used for kids without IV access
MOA: Bind to GABA A and allosterically make GABA work better
Abuse potential
Fat soluble vs. water soluble drugs
Fat soluble = Benzodiazepines, fast onset for seizures, crosses BBB fast; but leaves quick.
Water soluble = Lorazepam; takes longer to cross BBB but stays there longer.
What’s the go to for acute seizures?
Lorazepam
- Rectal dose of diazepam
- IV dose Lorazepam
-Takes longer to cross BBB but stays there longer.
Phenobarbital (Luminal)
- Opens up GABA A channels
- Drug of choice for neonatal seizures; can be used if patient fails a benzodiazepine (2nd line)
- Good for status epilepticus
- CNS depression, respiratory depression, hypotension
- Directly open channel, so more depressive effects.
- Metabolized by CYP2C19, Induces 2C9 and 3A4
C4
Pentobarbital (Nembutal)
- Similar to phenobarbitol in MOA/ADR
- IV for status epilepticus
- “Pentobarb coma”
Felbamate (Felbatol)
- Enhance GABA and inhibit NMDA glutamate receptors
- Risk for aplastic anemia, hepatotoxicity, drug interactions
Ethosuximide
- Blocks calcium channels
- DOC for absence seizures.
Gabapentin (Neurontin)
Pregabalin (Lyrica)
May interact with calcium channels and enhance GABA synthesis
- Renal excretion, DOSE RENALLY
- CNS depression
Lamotrigene (Lamictal)
- Inhibits sodium channels, inhibits glutamate release
- Inhibited by VPA, need to use 50% less of Lamotrigene so you don’t get toxicity!!!!!!!!
Black boxed: D/C at any sign of a rash.
- Rash, prevent by using low dose
- SJS
- Dizziness, ataxia, N/V
Patient on VPA still hving breakthrough seizures, want to add on Lamotrigene? How would you dose?
Use half of Lamotrigene to prevent toxicity.
Levetireacetam (Keppra)
Mechanism unknown
Quickly becoming a first line therapy
Adjunct for patrial seizures
Few drug interactions adn ADRs
Can increase aggression in children
Tiagabine (Gabitril)
- Inhibits reuptake of GABA
- Used as second line therapy when others failed by themselves
- Can cause psychosis
- Prevent toxic levels by taking it wtih food to slow rise in blood levels
Topiramate (Topamax)
- Sodium, gaba, and antiglutamate
- RENAL DOSING due to renal elimination
- Carbonic anhydrase activity
- Renal calculi and metabolic acidosis, esp with overdose
Also used for weight loss and migraines
Zonisamide (Zonegran)
Inhibits T calcium channels
Adjunct therapy, not used alone
Sulfonamide structure, so don’t give to those with SULFA allergy!!!!
Renal calculi
START OF NEWER DRUGS
Lacosamide (Vimpat)
Targets sodium and binds to collapsin response mediator protein
C5
Rufinamide (Banzel)
Triazole derivative
Modulate sodium channels
Somnolence, SUICIDE BEHAVIOR, QT shortening, STATUS EPILEPTICUS
Ezogabine (Potiga)
- Potassium channels
- QT prolongation, dysrythmias, aggressiveness
Perampanel (Fycompa)
- AMPA antagonist
- Aggression, hostility, homocidal ideation
TEST
Newer agents are less likely to be asked.
Phenytoin, carbamazepine, valproic acid = frequently used
Status epilepticus
- Airway and circulation under control first.
- 1st line: Lorazepam, diazapem per rectum, medazolam intransal.
- 2nd line: If unresponsive, phenytoin or fosphenytoin.
- 3rd line: If unresponsive, Levetireacetam or phenobarbital.
- 4th line: If unresponsive, valproic acid or phenobaritol.
- If unresponsive, general anesthesia or coma.
When do you stop AED therapy?
- Seizure free for 2 to 5 years.
- Single seizure type.
- Normal neuro exam.
- EEG normalized with treatment.
Can titrate off and see how they respond.
Drug Levels…..
….
What drugs cause less drowsiness?
Lamotrigene and valproic acid
What drugs are not used for school aged children due to their interference with learning?
Phenobarbital
What causes SJS?
Lamotrigene, carbamazepine, phenytoin, ethosuximide, phenobarbital
What caues life threatening rashes?
Oxcarbazepine, Lamotrigene
Aplasia anemia?
Felbamate
Use if they fail all the other treatmetns
Thrombocytopenia?
Carbamazepine, valproic acid, and phenytoin
Mouth ulcers, unusual bruising or bleeding
signs of blood dyscrasia
Hepatic failure?
Valproic acid
What drugs need TDM?
carbamazepine, phenobarb, valproic acid, phenytoin
What decrease effectiveness of oral contraceptives?
Phenytoin, phenobarb, carbamazepine, oxcarbazepine, felbamate
INDUCE CYP3A4 so metabolize it more quickly
Cholinergic toxidrome
Increasing levels of Ach, run risk of having muscarinic excess.
Defecation Urination Miosis Bradycardia Bronchorrhea and spasm emesis Lacrimation Salivation
leaking fluids from everywhere, pulmonary secretions are bad.
Cholinesterase inhibitors
- Tacrine
- Donepezil
- Rivastigmine
- Galantamine
- centrally acting, used to treat mild to moderate alzheimer’s disease.
- Improve memory/cognition
- Don’t affect course of continuing neurodegeneration, just extends life of Ach release.
-Does not stop disease progression.
G1 form
acetyl cholinesterase in the brain
Tacrine
Not used, because hepatotoxicity
Donepezil (Aricept)
Specific for acetyl cholesterase, no heptotoxicity or mild peripheral cholinergic affects.
metabolized by CYP2D6 and 3A4.
Rivastigmine (Exelon)
Inhibits acetylcholinesterase and BuChE
Dissocation or half life is 9 hours, longer duration of action and requires twice daily dosing
no cyp interactions
slow reversability
Galantamine (Razadyne)
Specific for AChE
Twice daily dosing
Have rapid reversability, may see reduced response over time.
Metabolized by CYP2D6 and 3A4.
Glutamate neurotoxicity drug therapy
Excitatory - destruction of neurons occurs from over excitatory or excess glutamtate activity - puts stress on neurons leading to neuronal loss.
Glutamate is responsible for it, so to slow progession of disease, can inbhit glutamate
Mamantine (Namenda)
moderate to severe alzheimers
well tolerated
glutamate antagonist - binds to receptor to change receptor so glutamate can’t bind.
Neuroprotective effects - able to slow down or stop neurodegeneration
