Pharm - Seizures Flashcards
Goals of therapy for seizure management
- complete elimination of seizures
- limit side effects
- optimal quality of life
what is the drug interaction b/w anticonvulsant agents and combo oral contraceptives?
anticonvulsants that induce hepatic enzymes decrease the efficacy of combo oral contraceptive pills
need for folic acid in women planning pregnancy while taking antiseizure meds
0.4 mg per day
what is the general titration strategy when initiating antiseziure med?
- start w/ monotherapy
- gradually increase the dosage to that which is maximally tolerated and/or produces seizure freedom
- start low, go slow
what is the general monitoring strategy when initiating antiseizure med?
- monitor tx regularly
- regular f/u visits to ck drug concentration, blood counts and hepatic/renal function
what is required when switching from Depakote to Depakote ER?
the dose should be increased by 14-20%
significant pharmacokinetics of valproic acid (depakote)
- extensively bound to albumin w/ saturable binding
- inhibits hepatic metabolism (P450 system)
- primarily metabolized in liver
- crosses placenta w/ higher fetal levels than mother
what is the significant of valproic acid being extensively and saturablely bound to albumin?
- the free fraction of valproic acid increases as serum concentration increases
- need to monitor unbound serum concentrations
- pts w/ low albumin will have more free drug in system
- important if on other meds that are competitive binders of albumin
therapuetic serum concentration of valproic acid
50-100 mg/L
valproic acid and pregnancy
AVOID
what are the most common ADRs for valproic acid?
- GI: n/v
- tremor
- thrombocytopenia
- weight gain
- hair loss
- liver toxicity
- PCOS
- hyperammonemia
tremor ADR from valproic acid
- one of the MC neurologic sx
- w/i the first year of tx
- looks like essential tremor
- reversible if dc drug
- reduce dose if possible or tx w/ propranolol
thrombocytopenia ADR from valproic acid
- usually mild reduction (100k - 150k)
- RFs: elderly, females, pts take >1g daily
- pt may present w/ petecchiae
- d/t bone marrow suppression or hypersensitivity reaction
weight gain ADR from valproic acid
- can be significant
- associated w/ increase in insulin levels
- in first 3 mos of tx
- women at higher risk
- common
hair loss ADR fro valproic acid
- associated w/ long term therapy
- dose related
- not complete loss, more alopecia
- reduce dose if possible
- recommend: biotin supplement, avoid taking valproic during meals, zinc/selenium supplement
liver toxicity ADR from valproic acid
- the most serious ADR
- can be fatal
- happens mostly in kids <2 on valproic acid and another anticonvuslant
- RFs: age <2, mental retardation, inborn errors of metabolism, several meds, difficult to control seizures
- early in tx
pharmacokinetic properties of topiramate (Topamax)
- 50% is excreted unchanged renally
- titrate slowly every 1-2 weeks
- linear kinetics
ADRs of topiramate
- CNS:
- word finding difficulty
- memory impairment
- thinking difficulties
- nephrolithiasis
- *anorexia/weight loss is a big one
- diarrhea
- paresthesias, fatigue, taste perversions
pharacokinetics of levetiracetam (Keppra)
- 2/3 is renally eliminated unchanged
- the rest is elimination of active metabolites
- metabolism is independent of the CYP system (limits potential for interaction w/ other antiseizure drugs)
- NOT an inducer of CYP system
- higher clearance in kids
- reduce dose in liver and renal insufficiency
ADRs of levetiracetam
- CNS side effects are most common
- agitation
- irritability or lethargy
- initiate dosing at 1/2 recommended dose
What are the advantages of levetiracetam
- linear kinetics
- not metabolized by P450 system
- no significant drug interactions
- well tolerated
- transient sedation is the most troublesome ADR
what are the disadvantages of levetiracetam?
- dosage adjustment needed in decreased renal function
- slower dose escalation to avoid CNS ADRs
what is important to remember about gabapentin (Neurontin)?
dose adjustments are required in patients w/ impaired renal function
ADRs of gabapentin
- main one: sedation
- use in caution w/ other meds
- dizziness
- ataxia
- weight gain
pharmacokinetics of perampanel (fycompa)
- extensively metabolized by liver
- primarily by CYP3A4
- prolonged and variable half-life (105 hrs)
black box warning associated w/ perampanel
-serious neuropsychiatric effects including alteration of mood and aggression
pharmacokinetics of carbamazepine (Tegretol) aka CBZ
- metabolized in liber by CYP3A4
- induces many enzymes causing rapid metabolism of other drugs
- an active metabolite - influenced by other drugs
- **induces its own metabolism (autoinduction )
autoinduction of CBZ
important!
- serum concentration rises over first 3-5 days
- followed by gradual decline over next month d/t autoinduction
- half life of the drug declines w/ chronic therapy
what is the outcome caused by CBZ autoinduction?
-pts may achieve adequate response at first but control declines
what is the therapuetic range of CBZ?
4-12 mcg/mL
how does autoinduction of CBZ effect the dosing strategy?
- usual starting dose: 2-3 mg/kg/day PO BID
- increase dose by 200 mg every 2-3 weeks to allow for autoinduction to take place
- do so until serum concentrations stabilize
- continue to monitor every 2-3 weeks after each dosage change
**very important to monitor serum concentrations and for pt to be consistent in taking the drug!
notable ADRs of CBZ
- hyponatremia
- leukopenia
- idiosyncratic (agranulocytosis, aplastic anemia, morbilliform rash, stevens-johnson syndrome)
hyponatremia d/t CBZ
- = serum Na < 134 mEq/dL
- incidence increases w/ age
- dose related
- increased responsiveness of collecting tubules to ADH
leukopenia d/t CBZ
- usually mild and reversible
- redistribution of WBC is the cause
- not a reason to stop drug unless WBC count drops <2,500 and absolute neutrophil count drops <1000
screening needed when starting CBZ
- HLA-B*1502 (main one)
- HLA-B*3101
- HLA-A*2402
*for risk of stevens-johnson syndrome
HLA-B*1502 screening
- screen pts w/ Asian ancestry d/t risk of stevens-johnsons syndrome
- if results are positive: AVOID drug
HLA-B*3101
- increased risk of stevens-johnsons across all ethnic groups
- some say test all CBZ-naive pts for this
HLA-A*2402
-independent RF for stevens-johnsons in southern Chinese HAN population
what is a major disadvantage of CBZ?
very teratogenic in the first trimester - higher incidence of spina bifida
what are the 2 drugs structurally similar to CBZ?
- eslicarbazepine (Aptiom)
- oxcarbazepine (Trileptal)
eslicarbazepine (Aptiom)
- NO autoinduction
- there is a risk of stevens-johnsons d/t structural similarity to CBZ
- also can cause hyponatremia
oxcarbazepine (Trileptal)
- NO autoinduction
- there is a risk of stevens-johnsons d/t structural similarity to CBZ
- also can cause hyponatremia
what is important to remember about michalis-menton (aka non-linear) kinetics?
a small change in dose can result in a disproportionally large increase in serum concentrations w/ potential to cause toxicity
therapuetic range of phenytoin (dilantin)
10-20 mg/L
what are the 4 oral dosage forms phenytoin?
- prompt release capsules (sodium salt)
- extended release capsules (2 strengths; sodium salt)
- suspension
- chewable tablets
considerations on changing dosage forms of phenytoin
**100 mg of phenytoin acid is equal to 92 mg phenytoin sodium
what is the impact of food and enteral tube feedings on phenytoin availability
bioavailability of phenytoin can be decreased in pts on continuous enteral tube feeding
phenytoin ADRs
- gingival hyperplasia
- vit. D deficiency
- osteomalacia
- hypothyroidism
- megaloblastic anemia
- hepatotoxicity
more rare but serious:
- rashes
- stevens-johnsons
- pseudolymphoma
- bone marrow suppression
- lupus-like syndrome
- hepatitis
pharmacokinetics of lamotrigine (lamictal)
- completely and rapidly absorbed (bioavailability 98%) not affected by food
- clearance is higher in children and lower in elderly
- doesn’t inhibit liver enzymes
- low potential for kinetic interactions w/ other drugs
- interacts w/ carbamazepine leading to increase in CNS ADRs
what is the nature of the drug-drug interaction of b/w lamotrigine and valproic acid?
valproic acid substantially inhibits the metabolism of lamotrigine
*max inhibition occurring at valproic acid doses and serum concentrations of 500 mh/day and 40-50mcg/ml
ADRs of lamotrigine in combo w/ other antiseizure meds
- diplopia (w/ CBZ)
- tremor (w/ valproic acid)
- rash
RFs for a serious rash w/ lamotrigine
- concomitant use of valprioc acid
- high initial doses or rapid doses used
- children have higher incidence
- more likely in those who had a rash d/t other tx
advantages associated w/ lamotrigine
- broad spectrum
- multiple dosage forms
- flexible
- linear pharmacokinetics
- not highly protein bound
- doesn’t inhibit metabolism of other drugs
CNS ADRs of phenobarbital
CNS depression: -confusion -dizziness -sedation -HA -hangover effect -impaired judgement -confusion -respiratory distress CNS agitation: -anxiety -hallucination -insomnia -nervousness -nightmares
what is the black box warning for vigabatrin (Sabril)
FDA boxed warning in the US regarding permanent vision loss
Which drugs can be monitored w/ serum concentrations?
phenobarbitol and ethosuximide
folic acid dose for prevention of neural tube defects in women taking anticonvulsants
4 mg/d beginning at least 1-3 before conception through first 3 mos of pregnancy
benefits of withdrawing anticonvulsant therapy
- offers pts a sense of being cured
- removes risk of ADRs
- drugs are expensive
risks of withdrawing anticonvulsant therapy
- possibility of seizures recurring
- risk for seizure control not being regained to the same degree
ID the meds used for status epilepticus
- Benzos: lorazepam, diazepam, midazolam
- phenytoin
- fosphenytoin
- phenobarbitol
