Pharmacology - Seizures and Epilepsy Flashcards
What are the S/E common to the ASMs?
Dizziness
Drowsiness=Somnolence
Headache
SJS/TEN
Blood dyscrasias
Hepatotoxicity (1st gen)
Osteomalacia (1st gen)
- Increased CL of vit D –> secondary hyperparathyroidism
- Increased bone turnover, reduced bone density
Which ASMs are assoc w NV?
CBZ, Valproate, Lamotrigine, Levetiracetam, Topiramate
What are the unique S/E for CBZ?
Diarrhoea, constipation, stomach upset, hyponatremia + PGx assoc SJS/TEN
What are the unique S/E assoc w PHT?
Hirsutism, gingival hyperplasia, wt loss, headache, insomnia, teratogenic
What are the unique S/E assoc w valprate?
Alopecia, ataxia, tremor, stomach upset, diarrhoea, wt gain, irregular or painful menstruation, pancreatitis, hyperammonemia, encephalopathy, suicidal ideation
What are the unique S/E assoc w lamotrigine?
Ataxia, tremor, asthenia, headache
What are the unique S/E assoc w levetiracetam?
Asthenia, ataxia, headache, irritability, aggression
What are the unique S/E assoc w topiramate?
Ataxia, cognitive dysfn (psychomotor slowing, speech, memory), wt loss, abdo pain, glaucoma, kidney stones, hyperammonemia, depression
What is the MOA of CBZ and PHT?
Inhib voltage gated Na+ channels
Decrease Na+ influx into cells
Decrease ability to generate AP
Decrease neuronal excitability
What is the MOA of valproate?
- Inhib voltage gated Na+ channels
- Decrease Na+ influx into cells
- Decrease ability to generate AP
- Decrease neuronal excitability - Inhib low voltage T-type Ca2+ channels
- Decrease influx of Ca2+ into cells
- Inhib exocytosis of excitatory neurotransmitters
- Decrease neurotransmission, neuronal excitability - Inhib GABA transaminase (enzyme which breaks down GABA)
- More GABA available to bind to GABA rece
- Opening of Cl- channels, Cl- influx
- Hyperpolarisation of membrane potential
- Reduced ability to generate AP –> recuced neuronal excitability
What is the MOA for levetiracetam?
Binds to SV2A protein in walls of vesicles that contain glutamate
Impair synaptic release of glutamate
Reduce neuronal excitability
What is the MOA of lamotrigine?
In addition to blockage of voltage dep Na+ and Ca2+ channels, inhib glutamate and impedes sustained repetitive neuronal firing
What are the indications for lamotrigine?
Adjunctive for partial seziures and generalised seizures
Monotherapy for typical absence seizures
Adjunctive or initial thera for Lennox-Gastaut syndrome
What are the indications for Levetiracetam?
Adjunctive thera for
- Partial onset seizures
- Myoclonic
- Primary GTC
Monothera for partial onset in NEWLY Dx epilepsy
What are the indications for topiramate?
Block voltage dep Na+ and Ca2+ channels
Block AMPA rece –> inhib excitatory neurotransm
Reduce neuronal excitability
What are the indications for topiramate?
Monotherapy for partial seizures, GTC
Adjunctive thera for Lennox-Gastaut syndrome
Migrain prophylaxis in adults
What is the MOA of benzodiazepines?
Bind to GABA rece @ regulatory site
- Potentiates Cl- influx
- Cl- influx hyperpolarises mem
- Reduce ability to gen AP
- Reduce excitability of cortex
Still req GABA (enhances inhib effect of GABA neurotransm)
Why are barbiturates more dangerous than benzodiazepines?
Linear r/s between barbiturate dosing/[ ] and CNS depression effects vs benzodiazepines hit a ceiling
What is the MOA of barbiturates?
Similar to benzodiazepines except that it binds to GABA rece at a site distinct from benzos and GABA
Still req GABA (enhances inhib effect of GABA neurotransm)
Describe the PK of PHT.
A:
- F: 95%
- Absorption reduced at doses >400mg/dose (split)
- Absortion reduced by enteral feeds –> space apart by 2h
D:
- Highly albumin bound (~90%)
- Vd: 0.7L/kg (0.5-0.8)
M:
- ~100% hepatic CL
E:
- t1/2: 12-60h
- Non-linear PK - 0 order kinetics
What are the points to note for phenytoin?
Highly albumin bound ~90%
- But in low albumin –> free phenytoin increases.
- May be displaced by valproic acid
- Original Winter-Tozer eqn etx used to est free PHT lvl in presence of hypoalbuminemia & renal impairment (found to not corr well)
- New studies to consider pt’s disease, dynamic parameters but still not ideal
Capacity limited CL = CL dep on [ ]
Increase [ ] –> Decreased CL. Metabolic enzymes saturated. [ ] increment NOT proportional to dose increment.
Relative narrow therapeutic range (plasma [ ] 40-100micromol), saturation kinetics & consequent non-linearr/s bet dose & plasma [ ]
What is the difference for saturation concerns between PHT and valproate (sodium)?
PHT: saturation of metabolic enzymes
Valproate: saturable plasma protein binding
Describe the PK of CBZ.
A:
- F: 75-85%
- Mean Tmax: 12h (tab), 24h (CR), 2h (susp)
- Food ingestion does not affect absorption
D:
- Highly protein bound: 75-80%
- Vd: 1.4L/kg (1-2Lkg)
- Crosses placental barrier
- [ ] in breastmilk is 25-60% of plasma levels
M:
- 100% hepatic, 99% by CYP3A4
- 30+ metabolites, active metabolite is CBZ10, 11-epoxide
E:
- t1/2: 6-15h
- 72% renal, 28% faeces
What are the points to note for CBZ?
Autoinduction of CYP3A4 enzymes. Induces own meta. CL increases, CBZ [ ] declines and stabilises in accordance w new CL & t1/e
Accel elim of other drugs as well
Req uptitration of dose
DO NOT start at desired maintenance dose at first. Gradually increase over a few weeks. Maximal autoinduction usually occurs 2-3 weeks after dose initiation
What are the DDI assoc w CBZ?
CYP3A4 inhib & substrate - Clarithromycin: increase serum [CBZ]
CYP3A4 inhib: increase serum CBZ
Warfarin: decreases warfarin meta
Can worsen anaemia
Who are the special populations in CBZ?
Pregnancy: Teratogenic
- Switch to lamotrigine or levetiracetam
Renal impairment: Not major route of elim (1-3%)
- Renal toxicities incl interstitial nephritis and hyponatremia (Use w caution)
Hepatic impairment: Use w caution
- Can cause hepatotoxicity since primarily metabolised by liver
Elderly: Beer’s List (list of drugs to be used w caution in pts >65y)
- Cause or exacerbate SIADH (syndrome of inadequate antidiuretic hormone secre) or hyponatremia
- Increased risk of psychiatric effects
What are the CI w CBZ?
Concomitant use of MAOis
Bone marrow depression
PGx: HLA-A*1502 & 3101 alleles
- If +ve: Avoid both CBZ and PHT shld be avoided as well
- If -ve: can be initiated on CBZ but shld be monitored durg 1st 12 weeks
Caution:
- Elderly
- Renal impairment
- Hepatic impairment
Describe the PK of valproate.
A:
- F: 90% relative to IV dose
D:
- Strongly bound to plasma proteins ~90-95%
Competition for binding e.g. PHT, warfarin, NSAIDs.
Displaced by endogenous compounds (uraemia, hyperbilirubinaemia)
- Free fraction: ~10%
- Vd= 0.15L/kg
M:
- Primarily hepatic via glucuronidation, mitochondrial β-oxidation and α-hydroxylation
E:
- t1/2: 9-19h in adults
What to take note of w valproate?
Saturable protein-binding within therapeutic range
↓protein binding at higher [ ], higher free fraction of drug w low albumin. Watch out for pts w low protein status (higher free fraction than anticipated)
What are the DDI assoc w valproate?
↓ [ ] of other antileptic drugs- Displaces other antiepileptics –> free drug higher than expected –> ↑CL
- Req dose adjustment
Warfarin: ↑ serum [warfarin]
- Valproate inhib CYP2C9 which metabolises S-warfarin
Azelastine (nasal), Orphenadrine: Enhance CNS depression
Hydroxyzine, opioid agonists: Enhance CNS depression
Carbapenem, Mefloquine: ↓ serum [valproate]
Lamotrigine, lorazepam: valproate ↑ serum [ ] of drugs
What are the CI assoc w valproate?
Pregnancy + Migraine prophylaxis
Severe hepatic impairment
PGx: rare mutations in POLG (codes for mitochondrial DNA polymerase chain gamma –> Alpers-Huttenlolocher syndrome (AHS) + risk of dev fatal VPA-hepatotoxicity
Urea cycle disorders, particularly OTC deficiency + risk of hyperammonemic encephalopathy
Who are the special populations wrt valproate?
Pregnancy
- Epilepsy and Bipolar disorder: CI unless no suitable alt
- Migraine prophylaxis: CI
Child bearing age (F)
- CI unless conditions of pregnancy prevention programme fulfilled
Males:
- Increase risk of neurodev disorders in children born to men treated w valproate in the 3mo prior to conception
Renal impairment: No dose adj
Hepatic impairment
- Mild-moderate: Not reco
- Severe: CI
Paeds
- Lower ini dose
- <3y.o. assoc w hepatotoxicity
Elderly: Lower ini dose, monitor for ADRs
What are the unique S/E assoc w benzodiazepines?
Severe respi depression (esp w alc)
Tolerance and dependence
- Tolerance: body needs higher dose to get same effect
- Dep: can dev –> withdrawal - disturbed sleep, rebound anziety, tremor, convulsions
- Must withdraw gradually
Ataxia, dysarthria, nystagmus, confusion, amnesia, suicidal ideation
How do we reverse respi depression from benzodiazepines?
Flumanezil (a benzo antagonist) - bind to benzo site, does not activate in the manner benzo does –> no potentiation of GABA
What are the S/E unique to barbiturates?
Dose dep CNS depression
Severe withdrawal symptoms
Suicidal ideation
Is flumanezil effective in treating barbiturate overdose?
No
Describe the PK of levetiracetam.
A:
- F ~100%
D:
- Highly sol & permeable
- < 10% protein binding
E:
- 66% renal
- t1/2: 4-8h
- PK profile linear w low intra & interpt var
Describe the PK of lamotrigine.
A:
- PO chewable tab (mainly used in paeds)
- F = 100%
D:
- 55% protein bound
M:
- 100% hepatic
E:
- t1/2 generally shorter in children
- t1/2 sig ↓ by coadmin w carbamazepine, phenytoin // ↑ by coadmin w valproate
- t1/2: 18-30h
Linear PK
Describe the PK of topiramate.
A:
- PO ROA
- F ≥ 80%
D:
- 15% protein bound
E:
- Long t1/2: 20-30h
- Predom renal CL (30-55%)
Linear PK
What are the dosing concerns with lamotrigine?
Risk of srs cutaneous rxn w
- High starting doses
- Rapid dose escalation
- Concomitant valproate
Slowly titrate, follow PIL
What are the DDI assoc w lamotrigine?
Carbamazepine, phenytoin:
- ↓t1/2 –> lower exposure
Valproate:
- ↑t1/2 –> prolong exposure
- Increased risk of srs cutaneous rxn
Discuss cutaneous skin rxns wrt ASM use
ASMs induce skin rxns by unknown mech. Hypothesised to be due to aromatic ring forming an arene-oxide intermediate (immunogenic upon interaction w proteins or cellular macromolecules)
- All 1st gen ASMs except valproate, oxacarbazepine
-Non-aromatic: valproate, levetiracetam, gabapentin, topiramate
Of the new generation ASMs which are hepatic CL dependent and which are not?
LTG: 100% hepatic
Levetiracetam and Topiramate are more renal dominant
Discuss reproductive concerns wrt ASMs
Women w epilepsy shld be referred to specialist care
- Discussion on fertility, contraception, family planning issues
- Early discussion on family planning
Potential risk to fetus (if pt has un controlled seizures)
Teratogenic potential of ASMs
Use of OC
- Potent enzyme inducers may render OC ineffective, alt methods req
- For pts on lamotrigine, OC may lower [lamotrigine] –> breakthru seizures
Discuss pregnancy wrt to ASMs.
- Levetiracetam and lamotrigine are safer options during pregnancy
- 1st gen ASMs and topiramate assoc w ↑ risk of major cogenital malformations (dose dep for CBZ, PB, topiramate)
- Neurodev risk for all the same pop as above except CBZ
- ↑risk of neurodev disorders (NDDs) in children born to men treated w valproate in 3mo prior to conception
Counsel potential risk, need for effective contraception (incl for female partner) while using and for 3mo after stopping treatment.
Do not donate sperm during and 3mo after stopping treatment. If planning to father a child, consult dr to discuss alt. In case of pregnancy, contact dr.
Discuss lactation wrt ASMs.
- All breast feeding women on ASM thera shld be encouraged to breastfeed
- Not indicated poorer outcome, pending long term outcomes
