Antiepileptics Flashcards
Idiopathic epilepsy Cause and breed predilection
Unknown cause- hereditary or genetic
Breed= Goldens, Labs, Germ shep, beagles etc
Idiopathic epilepsy onset of first seizure
1-5 years
IE- are there interictal neurologic deficits
No
IE- how is diagnosis made
Ruling out structural and metabolic causes
IE treatment
1= eliminate underlying cause
If can’t do that, want Symptomatic TX with anticonvulsants
When should I treat with anticonvulsants? (Name 3 things)
More than 1 seizure per month
Cluster seizures (lots in a short time period)
Status epilepticus
Therapeutic goals for seizures in vetmed
Acute- end seizure activity as rapidly and effectively as possible, w/o adverse effects
Maintenance- decrease FREQ and SEVERITY of seizures (RARELY ABOLISH in vetmed)
Manage Owner expectations!!
Acute vs chronic seizure management
Acute- HIGHLY lipid soluble, rapid CNS concentrations
Chronic - for maintenance
Pharmacological effect is ______ to drug concentration at site of action
Proportional
Drug concentration at site of action is ______ to the drug concentration in blood
Proportional
Measure drug concentration in blood!!
Therapeutic Drug Monitoring (TDM)— LOOK AT GRAPH
What is the importance of HL?
We recommend TDM after 5HL (takes 5HL for drug to reach SS levels). We want to know if our selected dose has achieved the DESIRED blood concentration at STEADY STATE (we want it in the THERAPEUTIC RANGE)
TDM: what is the importance of elimination half life? SEE GRAPH
Think of example with Phenobarbital
It determines DOSE INTERVAL
Ex. Phenobarbital elimination HL is 48 hours. But for some dogs, it can be less than 24 hours— need to SHORTEN the dosing interval (i.e. give q8 instead of q12) to KEEP IN THERAPEUTIC RANGE
Trough concentration (Cmin)- what is it, when does it occur
Plasma concentration of drug at LOWEST level during dosing interval
Occurs immediately PRIOR to the next dose
Peak concentration, what is it and when does it occur
Cmax or Cpeak
Maximum plasma concentration that occurs during the dosing interval
Occurs within a few hours after dosing
Relationship of efficacy vs toxicity and TROUGH/PEAK
Efficacy- Look at trough sample (are the drug concentrations staying within the therapeutic level?)
Toxicity- Look at peak sample (are the drug concentrations reaching toxic levels?)
TDM- loading dose (what is used for? When is it indicated? )
Used to get plasma drug concentrations into therapeutic range as fast as possible
Indications- in some patients, it would be detrimental to wait 5 drug HLs to reach SS
What is the risk of using loading dose?
Patient has not had time to adjust to pharmacological effects of the drug GRADUALLY —> risk of adverse effects= greater
Loading dose— dosing
One large dose or can be split into a few smaller doses over several days (Bromide)
Is TDM something that can only be done at speciality hospitals
No! Do not hesitate to take a blood sample and evaluate
What happens with abrupt withdrawal of anticonvulsants, and what can we do about that?
Precipitates status epilepticus
Make sure to educate client, wean attends off GRADUALLY
Name 3 maintenance anticonvulsants
PBL
Phenobarbital
Bromide
Levetiracetam
What does GABA do?
GABA stimulation —> opens Chloride channel —> hyperpolarization of neuronal cell
Glutamate
A stimulatory NT
Phenobarbital effects on GABA and glutamate
Enhances GABA (an inhibitory NT) effects —> CL channel open —> hyperpolarization of neuronal cell
Inhibits glutamate activity —> inhibits the stimulatory NT
Phenobarbital main MOA
Primarily stimulates GABA gated Chloride channel (GABA = inhibitor NT)
Basically, increases INHIBITION
Phenobarbital- metabolism
Metabolized by liver (C P450)
Phenobarbital PK Considerations (HL, SS, therapeutic concentrations) in dogs
HL average is 48 hours (range 12-125 hours)
5HL to SS
Therapeutic concentrations = 15-40 micrograms/mL
Phenobarbital in horses- HL
Shorter HL, so administer more frequently
Phenobarbital adverse effects that are CNS mediated (which wanes after a few weeks?)
CNS mediated: PU, PD, PP
Sedation and ataxia (often seen after starting therapy, but should decease after a few weeks)
Phenobarbital- Most common adverse drug reaction
Hepatotoxicity DOSE related (>30 micrograms/mL= higher risk)
Phenobarbital and effect on ALP and ALT
PB induces ALP (similar to glucocorticoids) and 2-5x is normal
Adverse if 5-10x baseline?
ALT- mild to moderate increases common
PB – make sure to monitor what with CBC CHEM
Liver enzymes and liver function! Bile acids, albumin, cholesterol
PB other adverse drug affects (notes)
CNS mediated PUPDPP, sedation, ataxia
BM: neutropenia and pancytopenia (less common)
Metabolism of thyroid hormones
PB and CYP450
induces CYP450 therefore is a “perpetrator” of drug interactions
but also metabolized BY CYP450 and is a “victim” of drug interactions as well
Monitoring time frame for PB
2 weeks (since HL is about 2 days, and want 5 HL) after starting PB or after any dose change (at SS): check PB level
Every 6 months- check CBC CHEM, UA, Bile acids (pre and post), PB level
*check for neutropenia too besides liver things
most common bromide
KBr
Bromide- MOA
transverses chloride channels resulting in hyperpolarization (inhibition) of neurons
Bromide metabolism
“not metabolized”
100% excreted by kidney = choice for liver disease
KBr half life and SS
25 days in dogs
SS= 4 months
For KBr, how does the HL influence dosing
HL is long (25 days) and since SS is 4 months, it is not often appropriate to wait 4 months to reach SS in a patient with seizures.
Use loading dose to achieve SS more quickly
For KBr, does TDM sample collection timing matter
no, doesn’t matter if you take concentration after dosing or AT trough…HL is too long (25 days)
KBr formulation options and preferred
Tablets, capsules, solution (preferred)
Tablets may damage gastric mucosa
KBr and GI effects
“salt”- hypertonicity may cause direct GI irritation and vomiting
GIVE WITH FOOD!
Bromide- adverse drug reactions
CNS depression (ataxia, sedation) PUPD, PP GI signs, pancreatitis Fatal resp distress in 30-50% in cats- AVOID use in cats NOT LIVER
Bromide CNS depression- when?
Occurs at higher doses, during initial dosing, and definitely AFTER LOADING
–> worse in beginning, then improves
Why avoid Bromide in cats
30-50% have FATAL resp distress
Does Bromide cause liver toxicity
No liver toxicity !
Bromide drug/diet interactions
Furosemide enhances bromide excretion, same goes for saline & increase in dietary salt
What can you see on clin path results due to bromide use
Br measured as Cl –> may see alarming Cl results, as high as 200mEq/L
Levetiracetam (Keppra) MOA
Interferes with presynaptic NT release
Levetiracetam - metabolism
NO HEPATIC METABOLISM
Primary RENAL elimination
Levetiracetam HL
about 4 hours in dogs (TID due to short HL), 5-6 hours in cats (TID), 7-8 hours in horses (BID)
Levetiracetam use by neurologists
Some use as 1st choice antiepileptic for dogs and cats, but clinical results are similar to other antiepileptics (not superior or inferior to bromide or PB)
Minimal side effects, safe for liver
Levetiracetam also known as
Keppra
Levetiracetam clinical results in cats
3 month trial- 7 out of 10 had positive response, tolerable side effects
Notes say that used less in cats, so monitor carefully
Maintenance anticonvulsants
Many others (human) drugs that are 3rd line for dogs Zonisamide = next most commonly used (besides PB, Br, and Keppra)
What are our initial choices for anticonvulsants
PB or KBr usually
Levetiracetam and Zonisamide are also reasonable choices
What happens if seizures continue in frequency or increase in severity with PB
Increase dose of PB until reaching the mid 30s ug/mL -or- side effects unacceptable
What happens if seizures continue in frequency or increase in severity with KBr
Increase dose of KBr until side effects are unacceptable
Use of multiple anticonvulsants- when can you add a second drug
When you maxed out on first drug (we rarely take them off an anti seizure drug)
sometimes need a third or fourth anticonvulsant
Aspen- case
Differentials for having cluster seizures while on PB
Subtherapeutic concentrations of PB
Refractory epilepsy
Progressive disease (not idiopathic epilepsy, i.e. parasitic )
Plan for Aspen- cluster seizures on PB
Trough phenobarbital level
If 13 ug/mL- increase PB dose
If 35 ug/mL- add 2nd drug, reconsider diagnosis
Consider MRI
If really high- could consider DRUG interactions with PB (drugs that inhibit cyt P450)
Acute seizure management– what route is preferred and drug
IV, Diazepam (valium)
What drug to avoid for acute seizure management and why
ORAL- delayed absorption, possible aspiration, risk of injury
What other routes for Diazepam
If IV difficult in seizing patient, or owners unable to administer it IV, consider:
IM/SQ (but erratic absorption, painful IM)
Rectal !!
Intransal
Rectal Diazepam pros
Reaches peak concentrations in systemic circulation in minutes, can send home w/ owners
Diazepam MOA
enhance GABA activity (inhibitor NT)
Diazepam PK considerations (3)
High lipid solubility
Short HL
Metabolized by liver
Diazepam – importance of high lipid solubility
Fast distribution to CNS (TX of choice for acute seizures!)
Diazepam– what to keep in mind with its HL
Short HL requires frequent administration
Not good as maintenance drug
Diazepam metabolism
Liver
Diazepam adverse reactions
Sedation (all species
Idiosyncratic hepatic necrosis (cats only)– RARE BUT FATAL!!
Idiosyncratic hepatic necrosis with what drug
Diazepam– cats
Diazepam drug interactions
Not a problem clinically
Diazepam practical considerations (think plastic etc)
Binds to plastic
Light sensitive
Levetiractam for seizure management
See study..
Rectal admin
Anesthetic agents for acute seizure management
3rd choice, for extremely refractory cases
I.e. Propofol and isoflurane
Note- propofol may cause seizures in cats
