ic7 - antiseizure medicines (ASM)

Question 1

classify the ASM into its different generations

Answer 1

first gen: CBZ, PHT, PB, VPA
second gen: GBP, TPM, LEV, LTG, pregabalin

Question 2

what drugs can we use for focal, GTC, tonic, atonic, absence, myoclonic

Answer 2

[focal] CBZ, VPA, LEV, LTG (TPM, GBP, PHT)
(refractory: pregabalin)

[GTC]
new: CBZ, VPA, LTG (TPM)
(refractory: LEV)

[tonic/ atonic] VPA first line, LTG adjunctive

[absence] LTG and VPA first line or adjunctive

[myoclonic] LEV and VPA and TPM first line or adjunctive

Question 3

compare the PK of the various ASM (A, F, protein binding, E, half life, ddi, enzyme type)

Answer 3

[CBZ] F 80%, protein binding 75-85%, E 100% H (autoinduction), half life 6-15h, ddi yes, enzyme inducer 1A2, 2C, 3A4, UGT, P-gp

[PB] F 100%, protein binding 50%, E 75% H, half life 72-124h, ddi yes, enzyme inducer 1A2, 2A6, 2B, 3A, UGT

[PHT] slow but complete A (slower at higher doses >400mg and with enteral feeds thus space 2hr apart), F 90%, protein binding 95%, E 100% H (non linear), half life 12-60h, ddi yes, enzyme inducer 2C, 3A, UGT, P-gp

[VPA] F 100%, protein binding 75-95%, E 100% H, half life 6-18h, ddi yes, enzyme inhibitor 2C9, UGT

[GBP] <60% A, no protein binding, E 100% R, half life 5-9h, no ddi

[LTG] 100% A, protein binding 55%, E 100% H, half life 18-30h, few ddi

[LEV] 100% A, protein binding <10%, E 66% R, half life 4-8h, no ddi

[TPM] >80% A, protein binding 15%, E 30-55% R, half life 20-30h, ddi dose dependent, enzyme moderate inducer 3A and moderate inhibitor 2C19

Question 4

what are the common ddi for ASMs

Answer 4

antidepressants and antipsychotics, immunosuppressive tx, antiretroviral tx, chemotx agents

Question 5

which ASMs are enzyme inducers

Answer 5

CBZ, PB, PHT

Question 6

what are the issues with enzyme inducing ASMs

Answer 6

reproductive hormones, sexual functions, OC in women (enzyme inducers act on liver enzymes and are not selective on whether it is a drug or hormone)

sexual func and fertility in men

bone health (can incr risk of osteopenia or osteoperosis if vitD and Ca not supplemented appropriately)

vascular risk

Question 7

what are the available dosage forms, indication, moa, F, A, Vd, protein binding, E, half life, enzyme, s/e, labs and monitoring of PHT

Answer 7

[dosage forms] PO suspension phenytoin acid (125mg/5mL, 100%), capsules (30, 100mg), IV phenytoin sodium (92%)

[indication] focal and GTC

[moa] blockade of Na channels

[F] 100%

[A] slow but complete (reduced at higher doses of >400mg and if given with enteral feeds thus space 2hr apart)

non linear PK (zero order kinetics and capacity limited CL aka CL dependent on conc and CL will decr with incr conc thus conc increment not proportional to dose increment)

[Vd] 0.7L/kg

[protein binding] 95% highly albumin bound (if low albumin will incr free PHT)

[E] 100% H (non linear)

[half life] 12-60h

[enzyme] inducer 3A4, 2C9, 2C19, UGT, P-gp

[s/e] gingival hyperplasia, hirsutism, osteopenia/ osteoperosis, arryhthmia, SJS, CNS (nystagmus, dizziness, HA, blurred vision, ataxia, incoordination), GI (N/V)

[labs] total (bound and unbound) PHT level, must adjust for corrected PHT estimate if hypoalbuminemia

[monitoring] osteopenia/ osteoperosis, lipid profile (LDL and cholesterol)

Question 8

what are the dosage forms, indication, moa, F, Vd, protein binding, E, half life, enzyme, s/e and monitoring for VPA

Answer 8

[dosage forms] inj (400mg/vial), enteric coated tablets 200mg), sustained release tablets aka chrono (200, 300, 500mg), syrup (200mg/5ml)

[indication] focal, GTC, myoclonic, absence

[moa] blockade of Na channels and GABA potentiation

[F] 100%

[protein binding] 90-95% (highly albumin bound, displacement by endogenous substances like in uremia and hyperbilirubinemia, competitive binding with PHT warfarin and NSAIDs, saturable protein binding)

[E] 100% H

[half life] 6-18h

[enzyme] inhibitor of 2C9, 2C19, UGT

[s/e] osteoperosis/ osteopenia, pancreatitis, weight gain, thrombocytopenia/ neutropenia, GI (N/V), CNS (ataxia)

[monitoring] osteopenia/ osteoperosis, PLT count, LFTs

Question 9

what should you do if there is hypoalbuminemia and PHT is to be used

Answer 9

if albumin <40g/L

C corrected = C observed/ [X(alb/10)+0.1]

where X is albumin coeff (X = 0.275 if CrCl 10, X = 0.2 if CrCl <10 *note 0.2 and 0.1 respectively if original winter-tozer)

units of alb in g/L and C in mg/L

Question 10

what are the dosage forms, indication, moa, F, protein binding, Vd, M, E, half life, enzyme, s/e and monitoring for CBZ

Answer 10

[dosage forms] immediate release tablets (200mg), controlled release tablets (200, 400mg)

[indication] focal, GTC

[moa] blockade of Na channel

[F] 80%

[protein binding] 75-85% (highly bound to albumin and alpha1 acid glycoprotein)

[M] >99% metabolised into active metabolite carbamazepine 10,11-epoxide by 3A4, autoinduction

[E] 100% H

[half life] 6-15h

[enzyme] inducer of 1A2, 2c9, 2C19, 3A, UGT, P-gp

[s/e] osteopenia/ osteoperosis, hypoNa, neutropenia, SJS, GI (N/V), CNS (nystagmus, dizziness, blurred vision, ataxia, incoordination)

[monitoring] osteoperosis/ osteopenia, LFTs, serum Na

Question 11

what is “autoinduction” and which ASM experiences this and how does it affect its dosing

Answer 11

induction of own metabolism -> causes CL to incr and half life to decr until conc decline and stabilise in accord with new CL and half life

CBZ has autoinduction and maximal autoinduction occurs 2-3w after initiation -> do not start with desired MD but start lower and titrate up slowly to ensure better tolerability

Question 12

what is “saturable protein binding” and which ASM experiences this

Answer 12

decr protein binding at higher conc of ASM and higher free frac of drug with low albumin (or other protein of interest)

VPA experiences this

Question 13

what is the indication, moa, A, protein binding, E, half life, enzyme and s/e of GBP

Answer 13

[indication] focal and GTC

[moa] P/Q type Ca channel blockade

[A] 60% or less

[protein binding] none

[E] 100% R

[half life] 5-9h

[enzyme] NA

[s/e] weight gain, peripheral edema, dizziness, ataxia

Question 14

what is the indication, moa, A, protein binding, E, half life, enzyme, s/e of LTG

Answer 14

[indication] focal, GTC

[moa] Na channel blockade and some effects on GABA potentiation

[A] 100%

[protein binding] 55%

[E] 100% H

[half life] 18-30h

[enzyme] inducer of UGT, inhibitor of 2C19 and UGT

[s/e] HA, insomnia, tremor, SJS, rash, GI (N/V)

Question 15

what are the indications, moa, A, protein binding, E, half life, enzymes, s/e and monitoring for TPM

Answer 15

[indications] focal, GTC

[moa] Na channel blockade and some effects on GABA potentiation

[A] 80% and above

[protein binding] 15%

[E] 30-55% R

[half life] 20-30h

[enzyme] moderate inducer of 3A4, moderate inhibitor of 2C19 (ddi is dose dependent)

[s/e] weight loss, memory problems, difficulty finding words, nephrolithiasis (kidney stones), CNS (somnolence, ataxia, fatigue)

[monitoring] metabolic acidosis

Question 16

what are the indications, moa, A, protein binding, E, half life, enzyme and s/e of LEV

Answer 16

[indications] focal, GTC

[moa] binding to SV2a protein

[A] 100%

[protein binding] <10%

[E] 66% R

[half life] 4-6h

[enzyme] NA

[s/e] psychiatric sx (behavioral disturbances)

Question 17

what are the types of s/e of ASM

Answer 17

dose/ plasma conc related, hypersensitivity related, chronic systemic, neurological, metabolic, endocrine, suicidal ideation

[dose/ plasma conc related] CNS (somnolence, fatigue, dizziness, visual disturbances, nystagmus, ataxia) GI (N/V) psychiatric (behavioural disturbances) cognition (speech fluency)

[neurological] peripheral neuropathy

[metabolic] weight gain, weight loss

[endocrine] osteomalacia

[suicidal ideation] FDA black box warning

[hypersensitivity] SJS/ TEN, exfoliative dermatitis, lupus like rxn, blood dyscrasia (aplastic anemia, agranulocytosis), pancreatitis, hepatotoxicity

[chronic systemic] gingival hyperplasia aka growth of gums, alopecia, hirsutism

Question 18

how to mitigate dose related s/e for ASMs

Answer 18

initiate at low dose and titrate slowly, avoid large dose changes, restrict tx to one drug only if possible, adjust administration schedule (largest dose at bedtime, divide daily dose into smaller doses given more freq, sustained release, reduce total daily dose)

Question 19

what are the drugs that can cause SJS and how can we risk manage

Answer 19

PHT, CBZ, LTG

PGx testing for CBZ, dosing guidance for LTG, identify potential cross sensitivity rxn for ASMs with aromatic rings

[PGx testing] HLAB*1502 for Han Chinese and other Asian ethnic groups -> conduct prior to starting and if positive avoid CBZ and PHT

[dosing guidance for LTG] risk of srs cutaneous rxn higher with high starting doses, rapid escalation and concom VPA

[cross sensitivity] ASMs with aromatic ring hypothesised to be able to form arene-oxide intermediate and become immunogenic through interactions with proteins or cellular macromolecules

Question 20

what is the dosing guidance for LTG

Answer 20

[if taking VPA] 25mg EOD weeks 1-2, 25mg QD weeks 3-4, incr by 25-50mg/d q1-2w weeks 5 until at MD, MD is 100-200mg/d w VPA alone, 100-400mg/d w VPA and other drugs that induce glucoronidation

[if NOT CBZ/PHT/VPA] 25mg QD weeks 1-2, 50mg QD weeks 3-4, incr by 50mg/d q1-2w weeks 5 until at MD, MD is 225-375mg/d

[if on CBZ/PHT but NOT VPA] 50mg QD weeks 1-2, 100mg/d weeks 3-4, incr by 100mg/d weeks 5 until at MD, MD is 300-500mg/d

Question 21

which ASMs are aromatic

Answer 21

CBZ, PHT, PB, LTG, oxycarbazine

Question 22

what is “nystagmus”

Answer 22

involuntary rhythmic side to side, up and down or circular motion of the eyes

Question 23

what is “ataxia”

Answer 23

poor muscle control that causes clumsy voluntary movements

Question 24

what is “dyskinesia”

Answer 24

involuntary, erratic, writhing movements of face, arms, legs or trunk

Question 25

what is “asthenia”

Answer 25

lack of energy/ strength

Question 26

what are the factors to consider and key determinants when choosing appropriate ASM for tx of epilepsy

Answer 26

[factors to consider] efficacy, tolerability, PK, personal preferences, nation specific factors

[key determinants] seizure type, epilepsy syndrome, drug profile effects on comorbs and other meds and tolerability in special populations, ddi and hormonal effects and renal/ hepatic impairment, formulation and dosing freq, guidelines and availability and costs

Question 27

what are the key components in the tx algorithm of epilepsy

Answer 27

after starting ASM, determine if seizure free -> determine if issue with intolerable s/e -> determine if optimal QoL -> determine if seizure free for >2 yrs

Question 28

when might ASM be discontinued

Answer 28

may be considered after a min of 2 yrs w/o seizure

but in pts with incr risk of seizure recurrence, advisable to wait longer than 2 yrs before considering discontinuation

decision to stop ASM involves balance of the risks of continuation (chronic toxicity, teratogenicity) with the implications of relapse

discussed with pts and carers/ family members and discussion details should be documented

tapering schedule should be individualised, taking into account risk factors for seizure recurrence, seizure freq, number of meds

Question 29

what are the details that should be documented when discussing discontinuation of ASM

Answer 29

when discussing discontinuation of ASM with pts and carers/ family members, should document

(i) reasons for discontinuation
(ii) taper schedule
(iii) plans for monitoring pts during and after taper
(iv) pts motivation for, attitude towards and understanding of the potential risks and benefits of discontinuation vs continuing tx

Question 30

what is the criteria to be met for epilepsy to be considered resolved

Answer 30

resolved for individuals who had an age dependent epilepsy syndrome but are now past the applicable age or those who have remained seizure free for last 10yrs with no seizure meds for past 5yrs

Question 31

why is there a need for TDM for ASM

Answer 31

difficult to identify optimal dose on clinical grounds alone bc

(i) plasma ASM conc correlate much better than dose with clinical effects
(ii) assessment of therapeutic response on clinical grounds alone is difficult in most cases (ASM tx is prophylactic, seizures occur at irregular intervals)
(iii) not always easy to recognise signs of toxicity purely on clinical grounds
(iv) ASMs subject to substantial PK variability and thus large differences in dosage are req in diff pts
(v) no lab markers for clinical efficacy or toxicity of ASM

Question 32

what are the indications for ASM TDM

Answer 32

(i) to establish individual’s therapeutic range -> ref range may not be effective for all, once stable document effective level which controls seizures while minimising s/e

(ii) to assess lack of efficacy -> fast metabolisers, lack of adherence

(iii) to assess potential toxicity -> changing physiology, slow metabolisers, changes in disease or drugs or renal/ liver or new drugs and interactions

(iv) to assess loss of efficacy (breakthrough seizures) -> changes in physiology (age, pregnancy), changes in pathology, changed formulation, drug interactions

Question 33

what are the information required in order to conduct ASM TDM

Answer 33

(i) indication for ASM (diagnosis)
(ii) dose (when, how long, how much)
(iii) sample and when was sample taken and what type of sample taken (if short half life, take trough to look at MD adequacy)
(iv) clinical condition (seizure control at baseline vs currently, comorbs)
(v) other lab values
(vi) other drugs (when, how long, how much)

Question 34

what are the ref ranges for the various ASM

Answer 34

PHT 10-20mg/L
VPA 50-100mg/L
CBZ 4-12mg/L
PB 15-40mg/L

Question 35

what are the special populations to consider for ASM

Answer 35

women of childbearing potential, pregnancy, lactation

[women of childbearing potential] referred to specialist care to (i) discuss fertility, contraception, family planning issues (ii) early discussion on family planning

use of OC may become ineffective due to ASM being potent enzyme inducers thus need alternative methods, OC may lower LTG conc resulting in breakthrough seizures, potential risk to fetus due to uncontrolled seizures and teratogenic potential of ASM

[pregnancy] LEV and LTG safer options, VPA should not be used bc high risk of serious developmental disorders and congenital malformations (CBZ, PB, PHT, TPM can cause major congenital malformations – all except PHT have dose dependent risk) (PB, PHT, TPM have neurodevelopmental risk)

[lactation] all breastfeeding women on ASM should be encouraged to breastfeed and encouraged to receive support from relevant HCPs

Question 36

what are the alternative contraception options for women of childbearing potential and wants to start on ASM

Answer 36

1. levonorgestrel or copper IUD
2. medroxyprogesterone depot inj q10-12w along with barrier method
3. continuous cycle COC (E and P) with at least 50mcg of E taken every day with 4d break q3m along with barrier method

Question 37

what is “status epilepticus”

Answer 37

it is when seizures continue or have different episodes that come and go and last >5mins

Question 38

what is the tx algorithm for status epilepticus (interventions for the different phases along the timeline)

Answer 38

stabilisation phase (0-5min), initial therapy phase (5-20min), second therapy phase (20-40min), third therapy phase (40-60min)

[stabilisation phase]
(i) stabilise pt (airway, breathing, circulation, disability -> neurologic exam)
(ii) time seizure from its onset and monitor vital signs
(iii) assess oxygenation, give O2 via cannula or mask and consider intubation if resp assistance needed
(iv) initiate ECG monitoring
(v) collect finger stick BG
(vi) attempt IV access and collect electrolytes, hematology, toxicology screen, ASM drug levels if appropriate

[initial therapy phase]
(i) if seizure continues, first line benzodiazepine
(ii) if not IM midazolam (10mg for >40kg, 5mg for 13-40kg single dose) or IV lorazepam (0.1mg/kg/dose max 4mg, may repeat dose once) or IV diazepam (0.15-0.2mg/kg/dose max 10mg, may repeat dose once)
(iii) if none above IV PB (15mg/kg/dose single dose) or rectal diazepam (0.2-0.5mg/kg max 20mg single dose) or intranasal midazolam or buccal midazolam
(iv) if seizure does not continue and pt at baseline then symptomatic medical care

[second therapy phase]
(i) if seizure continues, either IV fosphenytoin or IV VPA or IV LEV
(ii) if none above, IV PB
(iii) if seizure does not continue and pt at baseline then symptomatic medical care

[third therapy phase]
(i) if seizure continues, either repeat second therapy phase or anesthetic doses of either thiopental, midazolam, PB or propofol (all with continuous EEG monitoring)
(ii) if seizure does not continue and pt at baseline then symptomatic medical care

Question 39

what is the tx algorithm for status epilepticus (interventions for the different phases along the timeline)

Answer 39

stabilisation phase (0-5min), initial therapy phase (5-20min), second therapy phase (20-40min), third therapy phase (40-60min)

[stabilisation phase]
(i) stabilise pt (airway, breathing, circulation, disability -> neurologic exam)
(ii) time seizure from its onset and monitor vital signs
(iii) assess oxygenation, give O2 via cannula or mask and consider intubation if resp assistance needed
(iv) initiate ECG monitoring
(v) collect finger stick BG
(vi) attempt IV access and collect electrolytes, hematology, toxicology screen, ASM drug levels if appropriate

[initial therapy phase]
(i) if seizure continues, first line benzodiazepine
(ii) if not IM midazolam (10mg for >40kg, 5mg for 13-40kg single dose) or IV lorazepam (0.1mg/kg/dose max 4mg, may repeat dose once) or IV diazepam (0.15-0.2mg/kg/dose max 10mg, may repeat dose once)
(iii) if none above IV PB (15mg/kg/dose single dose) or rectal diazepam (0.2-0.5mg/kg max 20mg single dose) or intranasal midazolam or buccal midazolam
(iv) if seizure does not continue and pt at baseline then symptomatic medical care

[second therapy phase]
(i) if seizure continues, either IV fosphenytoin or IV VPA or IV LEV
(ii) if none above, IV PB
(iii) if seizure does not continue and pt at baseline then symptomatic medical care

[third therapy phase]
(i) if seizure continues, either repeat second therapy phase or anesthetic doses of either thiopental, midazolam, PB or propofol (all with continuous EEG monitoring)
(ii) if seizure does not continue and pt at baseline then symptomatic medical care