IC7 Flashcards
ILAE level A drugs for new onset focal onset epilepsy (adults)
carbamazepine *
phenytoin
lamotrigine*
levetiracetam *
valproate is level B *
- = also in NICE.
ILAE level A drugs for new onset focal onset epilepsy (elderly)
garbapentin
lamotrigine
ILAE drugs for new onset generalised tonic-clonic epilepsy (adults)
carbamazepine *
lamotrigine *
valproate *
topiramate
ILAE drugs for REFRACTORY focal onset epilepsy
clobazam
pregabalin (3rd gen)
perampanel (3rd gen)
lacosamide
only clobazam perampanel and pregabalin are available in Singapore.
however pregablin is less used for epilepsy
ILAE drugs for REFRACTORY generalised tonic clonic epilepsy
clobazam
levetiracetam
first line + adjunctive for tonic (NICE)
sodium valproate
add on lamotrigine
first line + adjunctive for atonic (NICE)
sodium valproate
add on lamotrigine
first line + adjunctive for absence (NICE)
sodium valproate
lamotrigine
add on are the same
first line + adjunctive for myoclonic (NICE)
sodium valproate
topiramate
levetiracetam
add on are the same
effect of ASM on hepatic metabolic enzymes
GEN 1:
INDUCERS:
Carbamezepine: inducer of cyp1a2, 2c9, 2c19, 3a, UGT
Phenobarbital: inducer of cyp1a, 2a6, 2b, 2c9, 2c19, 3a, UGT
Phenytoin: inducer of cyp2c9, 2c19, 3a, UGT
INHIBITORS:
Valproate: inhibitor of cyp2c19, UGT, epoxide
GEN 2:
Lamotrigine: inducer of UGT
Topiramate: inducer of cyp3a4 AND inhibitor of cyp2c19
problems with the first gen ASMs (state the drugs and elimination characteristics)
carbamazepine
phenytoin
phenobarbital
valproate
all have relatively high protein binding, high DDIs.
extensive oxidative metabolism
poor solubility
ALL are renally eliminated (100% ecepted phenobarbital )
which of the relevant 2nd gen and beyond ASMs are hepatically eliminated
lamotrigine
which of the new gen ASMs have effects on drug metabolims
only relevant one is topiramate (inducer of cyp3a and mod inhibitor)
gabapentin
levetiracetam
pregabalin
do not have any effect on CYP enzymes.
available dosing forms for phenytoin
oral suspension 125mg/5ml
100% phenytoin
capsules (30mg, 100mg)
IV phenytoin sodium (92%)
BA of phenytoin and how it is affected by different factors
F = 1
complete slow absorption
BUT
reduced at doses>400mg
AND
reduced by interaction with enteral feeds = to space apart by 2h.
vd of phenyotin and binding to albumin
Vd = 0.7L/kg
highly albumin-bound appx 90%
can be affected by displacement due to uremia, other drugs.
uremia, CKD affects levels of albumin
high urea toxins bind to albumin and displace phenyotin
phenytoin monitoring and how it is affected
state equation
total phenytoin level (bound and unbound)
- require use of predictive equations because only unbound phenytoin is active.
- no proper way to measure free phenytoin.
equation for albumin < 40g/L
C corrected = C observed/[x*alb/10 + 0.1]
if crcl≥10, x = 0.275
if crcl<10, x = 0.2
where alb is in g/L
C is in mg/L
what are the kinetics of phenytoin? how does this affect dosing?
zero order kinetics
non-linear
capacity-limited clearance.
as concentration increases, the clearance of the drug will decrease
AS SUCH, small therapeutic window and warrants careful titration. small increase in dose may lead to.a large increase in total and free phenytoin levels = neurological side effects/
dosage forms for valproate
injection 400mg/vial
enteric coated 200mg
SR 200.300.500mg
syrup 200mg/5ml
BA (F), Vd of valproate, protein binding
oral BA F = 1.0
vd 0.15L/kg
90-95% protein binding
what affects binding of valproate
displacement by endogenous compounds due to uremia, hyperbilirubinemia
eg urea toxins compete for binding with albumin
drugs: phenytoin, warfarin, NSAIDs
what kind of binding pK does valproate undergo? how does this affect dosing.
saturable protein binding within therapeutic range
decreased protein binding at higher conc
higher free fraction of drug with low albumin
also means that elimination will increase with increasing dose.
DO NOT titrate proportionally = free valproate levels unknown at higher ranges = more adverse effects.
carbamazepine dosage forms
IR 200mg
CR 200mg, 400mg
BA, protein binding, vd for carbamazepine
F = 0.8
75-80% protein bound
albumin alpha 1 acid glycoprotein
vd = 1.4L/kg
metabolism of carbamazepine
3a4
> 99%
metabolised into active metabolite = carbamazepine 10,11 epoxide
special characteristics of carbamazepine and how to dose
undergoes autoinduction, inducing its own metabolism
= clearance increase and t1/2 shorten = concentration stabilises in accordance with new CL and t1/2
maximal autoinduction around 2-3 weeks after initiation.
DOSING: do not start at maintenance dose but gradually increase over the first few weeks.
dosing strategies for ASMs
start low
titrate slow
avoid large dosage changes
restrict therapy to one drug
administration schedule = can take large dose at bedtime. OR divide daily dose into smaller doses. OR sustained release. OR reduce total daily dose
ADR of phenytoin
1) GI: N/V
2) Idiosyncratic reactions (SJS/TEN, hepatotoxicity, blood dyscrasias)
3) gingival hyperplasia (enlargement of gum tissue) AND hirsutism (including facial hirsutism) due to chronic therapy.
4) peripheral neuropathy due to chronic therapy (may improve with decreasing dose. response with folate supplementation)
5) Endocrine: osteomalacia (soft bone disease) from increased turnover of vit D = secondary hyperparathyroidism, increased bone turnover, reduced bone density.
6) megaloblastic anemia
7) neonatal congenital defects = major malformation risk (moderate), neonatal cognition
ADR of carbamazepine
1) GI: N/V
2) Idiosyncratic reactions
3) peripheral neuropathy due to chronic therapy
4) Endocrine: osteomalacia (soft bone disease) from increased turnover of vit D = secondary hyperparathyroidism, increased bone turnover, reduced bone density.
5) megaloblastic anemia
6) neonatal congenital defects = major malformation risk (moderate)
ADR of levetiracetam
Psych: behavioural disturbance (irritability, aggression)
ADR of topiramate
1) cognition: speech fluency
2) weight loss (reversible on discont)
3) neonatal congenital defects = major malformation risk (high)
ADR of valproate
1) Idiosyncratic reactions
2) alopecia with chronic therapy
3) peripheral neuropathy due to chronic therapy
4) weight gain (most commonly w valproate). will reverse spontaneously with discontinuation of tx
5) neonatal congenital defects = major malformation risk (high) , neonatal cognition
common ADR of most ASMs
almost all ASMs except some 2nd gen cause serious idiosyncratic reactions.
all gen 1 causes hepatotoxicity
others include: blood dyscrasia, pancreatitis, lupus like reaction, exfoliative dermatitis, TEN/SJS
blood dyscrasia vv common
though megaloblastic anemia is rare but occurs with gen 1 drugs (phenytoin, phenobarbital, carbamazepine)
SJS/TEN very common (range from mild maculopapular rash to SJSTEN
ALMOST all associated with suicidal ideation - close monitoring
how to lower rrisk of SJSTEN in ASM
– Risk management strategies:
1. Pharmacogenetic testing (carbamazepine)
2. Follow dosing guidance (lamotrigine)
3. Identify potential cross-sensitivity reaction (ASMs with aromatic rings)
what kind of genetic polymorphism involved in carbmazepine
hla-b*1502 carrier has increased risk of CBZ-induced SJS/TEN.
how to dose adjust for lamotrigine with other drugs
in patients taking valproate:
week 1 and 2: 25mg every other day
week 3 and 4: 25mg every day
week onwards to maintenance: increase by 25-50mg/day every 1-2 week
usual maintenance dose:
100-200mg/day with valproate alone; 100-400mg/day with valproate AND other drugs that induce glucuronidation (in 1-2divided doses).
in patients not taking CBZ, PH, PHB, primidone, valproate
week 1 and 2: 25mg every day
week 3 and 4: 50mg every day
week onwards to maintenance: increase by 50mg/day every 1-2 weeks
usual maintenance: 225-375mg/day in 2 divided doses
in patients taking CBZ, PH, PHB, primidone (BUT NOT VALPROATE)
week 1 and 2: 50mg/day
week 3 and 4: 100mg/day (divided 2)
week onwards to maintenance: increase by 100mg/day every 1-2 weeks
usual maintenance: 300-500mg/day (in 2 divided doses)
mechanism behind cross sensitivity reaction associated with aromatic ASMs
mechanism causing skin reactions unclear
might be due to formation of arene-oxide intermediate = become immunogenic through interactions with proteins or cellular macromolecules
discontinuation of ASM?
minimum 2 years
unless increased risk of seizure recurrence OR patient who had a low freq of seizures less than once a year before remission.
then wait longer than 2 years
should be SDM with patient and caretaker for reasons to discontinue, plans for monitoring… etc
reference ranges for TDM
phenytoin 10-20mg/L
valproate 50-100mg/L
CBZ 4-12mg/L
phenobarbitone 15-40mg/L
lamotrigine pertinent interaction w/ women of childbearing potential
OC may lower lamotrigine concentrations, resulting in breakthrough seizures.
ASM TDM indications
1) establish individual’s therapeutic range
- once stable, document. can help with any subsequent dosing changes.
2) assess lack of efficacy
- fast metaboliser? adherence issues?
3) assess potential toxicity
- changing physiology? slow metabolisers? change in disease or drugs?
4) assess loss of efficacy DUE to breakthrough seizure
- change in physiology/pathology/formulation/DDI?
what to counsel for women of childbearing potential
counselling on the importance of early discussion on family planning
potential risk of fetus - uncontrolled seizure and teratogenic potential
use of oral contraceptives
- some OCs may be rendered ineffective, will require alternative methods (eg add on barrier methods)
which ASM for pregnancy
levetiracetam and lamotrigine
what ASM should be avoided for pregnancy
valproate
CONTRA valproate in female children, PREGNACY or women of childbearing potential.
- for women of childbearing potential, conditions of the pregnancy prevention programme must be fulfilled. = counsel and contraception
- risk of serious developmental disorders and congenital malformation
NOTE phenobarbital pregnancy risk
counselling for male patients of reproductive potential
incr risk of neurodevelopmental disorders (NDDs) in
children born to men treated with valproate in the 3
months prior to conception
Patient education:
o potential risk + need for effective contraception, including
for the female partner, while using valproate and for 3
months after stopping the treatment
Patient to be advised:
o not to donate sperm during treatment and for 3 months
after stopping the treatment
o the need to consult his doctor to discuss alternative treatment options, as soon as he is planning to father a
child, and before discontinuing contraception
o he and his female partner should contact their doctor for counselling in case of pregnancy if he used valproate within 3 months prior to conception.
lactation counselling for ASM
ALL BREASTFEEDING women encouraged to breastfeed.
refer to specialist
for tonic clonic, what are the time frames for SE?
TIME seizure is likely to be prolonged leading to continuous seizure activity - 5min
TIME when a seizure may cause long term consequences
= 30min
definition of status epilepticus
failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to ABNORMALLY PROLONGED SEIZURES
will have long term consequences: neuronal death, injury, alteration of neuronal networks.
treatment algorithm for AES
0-5MIN STABILISATION PHASE:
- stabilise ABC
- time seizure, monitor vitals.
- ECG, O2, BGM
(if BG<60mg//dL, then adult 100mg thiamine IV then 50ml D50W IV OR child ≥2yo 2ml/kg D25W IV) normal BG around 70-100.
- IV
- collect electrolytes, hematology, toxicology screen, anticonvulsant drug levels
5-20MIN INITIAL THERAPY
- if seizure continues then initiate benzodiazepines
1) IM midazolam single dose; 10mg for >40kg, 5mg for 13-40kg
2) IV lorezapam (may repeat dose once). 0.1mg/kg/dose, max 4mg/dose.
3) IV diazepam (may repeat dose). 0.15-0.2mg/kg/dose, max 10mg/dose
20-40MIN SECOND THERAPY
- no evidence for preferred second line
choose
1) IV fosphenytoin 20mg PE/kg max 1500mg PE/dose single dose
2) IV valproic acid 40mg/kg max 3000mg/dose single dose
3) IV levetiracetam 60mg/kg max 4500mg/dose single dose
40-60min THIRD THERAPY
- repeat second line agents
recommendation for prescribing of carbamazepine
STRONG RECOMMENDATION for HLA-B15:02 (high prevalence in Asian ancestry) AND HLA-A31:01 carriers to avoid carbamazepine
- choose alternative
UNLESS
patient has been taking carbamazepine for >3 months = continue therapy (usually onset of induced hypersx is within the first month) - there is a chance of cross reactivity with HLA-B*15:-02 carriers using aromatic anticonvulsants (phenytoin, phenobarbital, lamotrigine)
alternatives to carbamezepine for various indications
neuropathic pain: gabapentin
mood stabiliser: lithium, valproate, quetiapine, aripiprazole, olanzapine
epilepsy: levetiracetam, valproate, topiramate, perampanel
topiramate other known side effects:
glaucoma
hyperammonemia
metabolic acidosis
hyperthermia (decreased sweat production)
paraesthesia
renal stones
