Seizures PHARM Flashcards
Neurotransmitters CNS
vs. PNS
CSN: 21 neurotransmitters
PNS: 3 neurotransmitters (E, NE, Ach)
- Monoamines
- NE, E, DA, 5HT3 - Amino acids
- glycine, glutamate, GABA, aspartame - purines
- adenosine, AMP, ATP - opioid peptides
- endorphins, enkephalins, dynorphins, etc. - non-opioid peptides
- oxytocin, somatostatin, substance P, ADH (etc.) - other:
- histamine, acetylcholine
Excitatory/Inhibitory Post Synaptic Potential
Pathophysiology
Dendrites
- Ligand (NT) gated ion channels
- NT binds Na/C ion channels
- Excitatory post synaptic potential: influx Na+, influx Ca+ (more positive)
- Inhibitory post synaptic potential: efflux K+ (more negative)
*Depolarization towards threshold -55mV = fire action potential
Resting Membrane Potential
Pathophysiology
-70mV
Na/K ATPase
3 Na+ out
2 K+ in
High concentration Na+ outside cell
High concentration K+ inside cell
Action Potential
Pathophysiology
Excitatory Post synaptic potentials
- depolarization through influx Na+ and Ca+ ligand gated ion channels
- moves towards -55mV (depolarization towards threshold)
Action potential fires
- Voltage gated sodium channels OPEN
- influx of sodium
- depolarization to +40mV
- voltage gated sodium channels CLOSED INACTIVE STATE (absolute refractory)
Hyperpolarization
- Voltage gated potassium channels OPEN (slower)
- efflux of K+
- hyper polarization (beyond -70mV) voltage gated sodium channels CLOSED (relative refractory period)
- voltage gated potassium channels CLOSE
Na/K ATPase
- restores resting membrane potential -70mV
- 3 Na+ out
- 2 K+ in
Excitatory vs. Inhibitory NT
Excitatory NT
- Glycine
- Glutamate
Inhibitory NT
- GABA
- NE
- HT
- cannabinoids
- opioids
*Dependent on the pre-synaptic receptor
Drugs that affect sodium influx
CLOSED INACTIVE voltage gated sodium channels
Drugs that keep voltage gated sodium channels in inactive state (CLOSED)
- Phenytoin
- Carbamazepine (Eslicarbazepine, Oxcarbazepine)
- Lamotrigine
- Lacosamide
- Rufinamide
- Topiramate
Drugs that affect Calcium influx
Ethosuximide
Drugs that affect GABA
- Benzodiazepines (ex. diazepam)
- Barbiturates (phenobarbitol, primidone)
- Gabapentin
- Valproic Acid
- Vigabatrin
Drugs that affect glutamate receptors
- topiramate
- perampanel
Drugs with unknown mechanism of action for AED
- levetiracetam
- bivaracetam
- pregabalin
Drugs for Absence seizures
ethosuximide (block calcium influx)
valproic acid (agonist GABA)
AED used for all seizure types
VPA
Valproic acid
Goal of AED therapy
Decrease seizure frequency, severity, duration
*not seizure free
Minimize SE and impact on ADLs
Pregnancy and AEDs
monotherapy
lowest dosage
avoid valproic acid at all costs
folic acid supplementation
Vitamin K supplementation
90% will have normal pregnancy
Pregnancy and Epilepsy
Increase risk of abortion, still birth, preterm labour
Phenytoin/Fosphenytoin
MOA
Targets hyperexcitable neurons in the seizure focus
Keeps voltage gated sodium channels closed and INACTIVATED
Cannot fire new action potential
Phenytoin / Fosphenytoin
SE
EYES: Nystagmus, blurred vision, diplopia
MSK: Ataxia
CNS: confusion, sedation
CARDIO: cardiovascular collapse with fast infusion
HEME: Bleeding risk (suppression Vitamin K coagulation factors), infection risk (bone marrow suppression)
ENDOCRINE: Hirsutism, gum hyperplasia and bleeding
Special considerations IV infusions
Phenytoin
Fosphenytoin
- Phenytoin (IV, PO)
IV filter
slow IV infusion to prevent cardiovascular collapse - Fospheytoin (IV, IM)
paraesthesia and pruritis of groin during IV infusion
Pro-drug conversion, no filter needed
decreased risk cardiovascular collapse
can infuse faster
Phenytoin/Fosphenytoin
AE
HLA-1502
1. SJS, TENS, DRESS
Patient education: monitor for rash
*Asian Descent
- Teratogenic
Patient education: condoms, oral contraceptives degraded - Infection and bleeding risk
Monitoring: CBC, INR
Patient education: report bruising, signs of infection - fractures
- Phenytoin blocks vitamin D activation
- results in hyperparathyroidism (secondary)
- calcium is not absorbed from GI
- bones are reabsorbed
Therapeutic Drug Monitoring
Phenytoin
Saturation Kinetics
- saturate hepatic enzyme quickly
- small change in dose, large change in drug level
Narrow therapeutic window
- small dose can cause 1. toxicity 2. therapeutic failure
Therapeutic drug monitoring
- plasma level
- trough level
*Drug interactions high
Administration considerations
Phenytoin/Fosphenytoin
Do not administer with food
1-2 hour hold
PRN
calcium
vitamin D
IV filter for phenytoin
Pharmacy to check drug interactions
saturation kinetics
Carbamazepine
MOA
Target: seizure focus (hyper excitable neurons) and surrounding neighbours
Keeps voltage gated sodium channels in INACTIVE and CLOSED state (prolongs absolute refractory period)
prevents firing of new action potential
Carbamazepine
SE
EYES: Nystagmus, blurred vision, diplopia
CNS: sedation
MSK: ataxia
- tolerance develops
- Patient education: start low, go slow, night admin
Bone marrow suppression: bleeding and infection risk
Teratogenic: NTD
SKIN: SJS, DRESS, TENS (HLA-1502)
OTHER:
Kidney failure
Increase ADH release: FVO, hyponatremia
Liver failure
Carbamazepine
AE
Teratogenic: NTD
Patient education: folic acid, contraception condoms, oral
Kidney failure: FVO, hyponatremia, ADH hyper secretion
Patient education: weight gain, oliguria, S&S hyponatremia
Liver failure
Bone marrow suppression: Bleeding and infection (Fatal aplastic anemia D/C)
HLA1502: TENS, DRESS, SJS
Patient Monitoring
Carbamazepine
CBC and diff
HLA-1502 status
LFTs
BUN, creatinine
serum sodium
serum ferritin
Weight
HCG
S&S liver failure: jaundice, anorexia, n/v
S&S kidney failure: weight gain, oliguria
S&S bleeding: bruising, pale, fatigue
S&S infection: fever, sore throat
S&S hyponatremia: fatigue, anorexia, loss muscular tone, depressed reflexes, orthostatic hypotension, etc.
Carbamazepine
Indications
All seizures
*Exception - absence seizures
Carbamazepine
Hepatic Metabolism
Induces its own metabolism
Induces metabolism of other AEDs
- phenytoin
- phenobarbital
- oral contraceptives
Carbamazepine
Contraindications
Liver disease
Kidney disease
pregnancy
HLA1502
Blood disorders
Caution secondary Hyperparathyroidism
Heart failure
Hypertension
Ethosuximide
MOA
Blocks calcium channels in pre-synaptic (Blocks EPSP) and post synaptic membrane (Blocks NT release)
Prevents transmission of excitatory impulse
Ethosuximide
Indication
Absence seizures
Ethosuximide
SE
EYES: Nystagmus, blurred vision, diplopia
CNS: sedation
Patient education: take at night, tolerance develops
GI: nausea, vomiting, weight loss
Patient education: take with food
SKIN: Rash
HEME: Bone marrow suppression, SLE
Patient monitoring
Ethosuximide
Clinical response
- no drug monitoring
- absence seizures occur at high frequency
CBC and diff
Patient monitoring
S&S bleeding, infection, rash, weight loss
Phenobarbital/Primidone
MOA
GABA agonist
increase activity of GABA
CNS depressant
*Phenobarbital is a metabolite of primidone
Phenobarbital/Primidone
SE
CNS: sedation, dizziness, fatigue, learning impairment
Patient education: take at night, tolerance develops
PSYCH: depression/suicide adults, paradoxical agitation children/older people
HEME: porphyrin accumulation
RESP: respiratory depression
Phenobarbital/Primidone
AE
Respiratory depression and death
Contraindicated: respiratory disorders, CNS depressants, liver/kidney disease (drug accumulation)
Addiction, depression, suicide
Contraindicated: psych history
Withdrawal
Phenobarbital/Primidone
Contraindications
Respiratory disorders
liver and kidney disorders (drug accumulation)
history addiction, suicide, depression
Patient Monitoring
Phenobarbital/Primidone
CBC and diff
LFT
BUN and Creatninine
Respiratory disorders
Medication: CNS depressants
Hx. addiction, mental health
Primidone
MOA
Phenobarbital is a metabolite of primidone
GABA agonist
increase CNS depression
Indication
Phenobarbital vs. Primidone
Phenobarbital
- All seizures exception absence
Primidone
- all seizures exception absence and status
Valproic Acid
Indication
ALL SEIZURES
* absence included
Rx combination seizures
Valproic Acid
MOA
Unknown
Thought to be a GABA agonist
Increase CNS depression
Valproic Acid
SE/AE
CNS: *Minimal sedation
MSK: tremor
GI: N/V/anorexia/abdominal pain, weight gain
Patient education: administer with food
HEME: bone marrow suppression
Kidney: Ammonia accumulation
Hepatitis and liver failure
pancreatitis
Teratogenic
Valproic Acid
AE
Teratogenic: 4x higher than other AEDs
Kidney: Ammonium accumulation and encephalopathy (N/V/anorexia, HA, ataxia, seizures, coma)
Liver: hepatitis and liver failure (anorexia, N/V, jaundice, dark urine, pale stools)
Pancreatitis: debilitating RUQ pain, radiation back, hypotensive shock, ARDs, DIC, GI hemorrhage, multiple organ failure
Contraindications
Valproic acid
- Pregnancy
- teratogenic 4x - < 2 years of age and multiple AEDs
- hepatitis and pancreatitis
- death - Liver disease, pancreatic disease
- blood dyscarias
Patient monitoring
VPA
CBC and diff
LFTs
BUN and creatininine
serum lipase
HCG
Patient education
VPA
S&S: bleeding, bruising, pallor, fatigue, infection (bone marrow suppression)
S&S: anorexia, nausea, vomiting, jaundice (liver failure)
S&S: RUQ pain, hypotensive shock, DIC, fever (pancreatitis)
pregnancy: oral contraceptive and condom
S&S encephalopathy ammonium: ataxia, N/V/HA, coma, seizures
levetiracetam
MOA and indication
unknown MOA
All seizures exception absence
Levetiracetam
safety profile
safest AED
doesn’t require hepatic metabolism
doesn’t interact with other AEDs
Levetiracetam
SE
CNS: Sedation
Psych: aggression, agitation, anxiety, depression, psychosis
MSK: asthenia (lack of strength)
Kidney: query renal failure
Seizure Threshold and Pregnancy
Pregnancy hormones (estrogen) lowers the seizure threshold
Increased plasma volume lowers the AED level
*predisposes people to seizures
Seizure effect on fetus and mother
Increase risked of fetal and maternal death
Fetus
- decrease heart rate, perfusion
- increase risk of pre-term labour, stillborns, miscarriage
Mother
- increased risk of death
AED Strategy during pregnancy
AEDs teratogenic
- phenytoin
- carbamazepine: NTD (folic acid supplementation)
- Valproic acid: absolute contraindication 4x risk
Monotherapy
lowest dose
Vitamin K and folic acid supplements
AEDs that lower oral contraceptive levels (hepatic metabolism)
- Phenytoin
- carbamazepine
- valproic acid
- phenobarbital/ primidone
- toperiamate
- lamotrigine
Ketogenic Diet
Therapeutic effect
Indication: Medication resistant epilepsy
Decrease seizure frequency, severity
Diet high in fat, protein, low in carbohydrate
Induce a state of ketosis
Ketone bodies produced
Increase the seizure threshold
Ketogenic Diet
SE
Metabolic acidosis
- ketone bodies (keto acids)
Hypoglycemia
- SNS effects: diaphoresis, sweating, tachycardia
- CNS effects: lethargy, sedation, coma
Systemic:
- CAD, atheroscelerosis, dyslipidemia
- pancreatitis
- kidney stones (high protein)
Weaning AED
six weeks to wean
wean 1 drug at a time
Driving and Epilepsy
- 6 to 12 months seizure free before can drive
- 16 years of age mandatory reporting in Ontario (even if do not have licence)
